The American Journal of Medicine
Volume 121, Issue 1 , Pages 24-33, January 2008

Statin Therapy in Stroke Prevention: A Meta-analysis Involving 121,000 Patients

  • Christopher O’Regan, MSc

      Affiliations

    • Department of Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
    • ,
  • Ping Wu, MBBS, MSc

      Affiliations

    • Department of Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
    • ,
  • Paul Arora, MSc

      Affiliations

    • Centre for Global Health Research, University of Toronto, Ontario, Canada
    • ,
  • Dan Perri, BScPhm, MD

      Affiliations

    • Department of Medicine, McMaster University, Hamilton, Ontario, Canada
    • ,
  • Edward J. Mills, MSc, PhD

      Affiliations

    • Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
    • Dr. Mills is supported by the Canadian Institutes of Health Research.
    • Corresponding Author InformationRequests for reprints should be addressed to Edward J. Mills, MSc, PhD, Department of Clinical Epidemiology and Biostatistics McMaster University, 1200 Main Street West, Rm. 2C12, Hamilton, Ontario L8N 3Z5, Canada.

Article Outline

Abstract 

Purpose

More than 120,000 patients now have taken part in randomized trials evaluating statin therapy for stroke prevention. We aimed to conduct a comprehensive review of all randomized trials and determine the therapeutic potential of statins for all strokes.

Methods

We searched 10 electronic databases (from inception to December 2006). We additionally contacted study authors and authors of previous reviews. We extracted data on study characteristics and outcomes related to all-cause mortality, all-stroke incidence, specific type of strokes, and cholesterol changes. We pooled data using a random-effects model and conducted meta-regression.

Results

We included 42 trials assessing statin therapy for all-stroke prevention (n=121,285), resulting in a pooled relative risk (RR) of 0.84 (95% confidence interval [CI], 0.79-0.91). The pooled RR of statin therapy for all-cause mortality (n=116,080) was 0.88 (95% CI, 0.83-0.93). Each unit increase in low-density lipoprotein (LDL) resulted in a 0.3% increased RR of death (P=.02). Seventeen trials evaluated statins on cardiovascular death (n=57,599, RR 0.81, 95% CI, 0.74-0.90), and 11 evaluated nonhemorrhagic cerebrovascular events (n=58,604, RR 0.81, 95% CI, 0.69-0.94). Eleven trials reported hemorrhagic stroke incidence (total n=54,334, RR 0.94, 95% CI, 0.68-1.30) and 21 trials reported on fatal strokes (total n=82,278, RR 0.99, 95% CI, 0.80-1.21). Only one trial reported on statin therapy for secondary prevention.

Conclusions

Statin therapy provides high levels of protection for all-cause mortality and nonhemorrhagic strokes. This overview reinforces the need to consider prolonged statin treatment in patients at high risk of major vascular events, but caution remains for patients at risk of bleeds.

Keywords: All-cause mortality, 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, Meta-analysis, Statins, Stroke

 

Of the approximately 700,000 strokes per year in the United States, the majority are initial episodes, whereas some 200,000 are recurrent events. Ranked third behind heart disease and cancer for leading causes of death, up to 30% of stroke survivors are permanently disabled, and within 3 months of onset, 20% of stroke patients will require institutionalization.1

Clinical Significance

 


•In a comprehensive meta-analysis, statins effectively reduced risk of all-cause death and of nonhemorrhagic stroke.

•Every unit increase in low-density lipoprotein (LDL) increased relative mortality risk by 0.3%, but neither LDL change nor any other covariate affected stroke risk.

•Few head-to-head trials exist to guide practice about the relative benefits of specific statins.

•Other known effects of statins might be more important than LDL reduction in protecting against ischemic stroke.

•Despite the compelling evidence of primary therapeutic protection for strokes, secondary prevention trials are desperately needed.

Epidemiologic studies have not demonstrated a clear relationship between the risk of ischemic stroke and dyslipidemia.2, 3 However, a variety of large coronary artery disease prevention trials and subsequent meta-analyses demonstrate an association of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) with a reduction in stroke risk.4, 5, 6, 7, 8, 9, 10, 11, 12, 13 Preliminary data to support stroke risk reduction with statins in the absence of coronary artery disease also is available through meta-analytic data.14 Large, simple trials, such as the Heart Protection Study and Anglo-Scandinavian Cardiac Outcomes Trial provide strong support for statin therapy in reducing stroke risk in patients with average or low LDL (low-density lipoprotein) cholesterol levels.7, 9, 10 Taken together, these data suggest a role for statins in stroke prevention independent of coronary artery disease risk reduction or serum lipid levels. Statins have been associated with a variety of pleiotropic effects, including atherosclerotic plaque stabilization, decreased inflammation, improvement in endothelial function, and altered thrombogenicity.15

Before entering an exciting era of statin stroke prevention, it is important to determine if, from the totality of evidence to date, all statins have a role in primary and secondary stroke prevention, and if any benefits are dose dependent. Using a systematic review of the literature and meta-analytic techniques, we aimed to quantify the effects of statin therapy on both primary and secondary stroke prevention, and any associated mortality benefit. We further sought to determine differences in stroke risk reduction among a variety of statins, dosing strategies, and types of stroke.

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Methods 

Eligibility Criteria 

We included any randomized trial of atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. We included randomized trials of any duration. Studies had to compare a statin to placebo or no treatment, and report on any of the following clinically important cardiovascular outcomes: all-cause mortality, all-stroke incidence, fatal strokes, hemorrhagic, or ischemic strokes. We excluded studies reporting only on surrogate outcomes (eg, LDL and high-density lipoprotein [HDL] levels).

Search Strategy 

In consultation with a medical librarian, we established a search strategy (available from corresponding author on request). We searched independently, in duplicate, the following 10 databases (from inception to December 2006): MEDLINE, EMBASE (Exerpta Medica), Cochrane Central Register of Controlled Trials (CENTRAL), Allied and Complementary Medicine Database (AMED), Cumulative Index to Nursing and Allied Health Literature (CINAHL), TOXNET, Development and Reproductive Toxicology, Hazardous Substances Databank, Psych-info, and Web of Science, databases that included the full text of journals (OVID, ScienceDirect, and Ingenta, including articles in full text from approximately 1700 journals since 1993). In addition, we searched the bibliographies of published systematic reviews11, 12, 13, 14, 16, 17, 18, 19, 20 and health technology assessments.21 We also contacted the authors of all trials for study clarifications, where required, and the authors of the only individual-patient data meta-analysis of statins for stroke, which included 14 trials.20 Searches were not limited by language, sex, or age.

Study Selection 

Two investigators (EM, PW) working independently, in duplicate, scanned all abstracts and obtained the full text reports of records that indicated or suggested that the study was a randomized trial evaluating statin therapy on the outcomes of interest. After obtaining full reports of the candidate trials (either in full peer-reviewed publication or press article), the same reviewers independently assessed eligibility from full text articles.

Data Collection 

The same 2 reviewers conducted data extraction independently using a standardized prepiloted form. Reviewers collected information about the statin and type of interventions tested, the population studied (age, sex, underlying conditions), the treatment effect on specified outcomes, change in LDL, high density lipoprotein, and total cholesterol, and the length of follow-up. Study evaluation included general methodological quality features. We entered the data into an electronic database such that duplicate entries existed for each study; when the 2 entries did not match, we resolved differences through discussion and consensus.

Data Analysis 

In order to assess inter-rater reliability on inclusion of articles, we calculated the Phi statistic, which provides a measure of inter-observer agreement independent of chance.22 We calculated the relative risk (RR) and appropriate 95% confidence intervals (CIs) of outcomes according to the number of events reported in the original studies or sub-studies. In the case of an individual-patient data meta-analysis of 14 trials, we included outcomes as reported by the meta-analysis, in correspondence with all the study’s authors. In the event of zero outcome events in one arm of a trial, we used the Haldane method and added 0.5 to each arm.23 We pooled studies as an analysis of all-statins combined using the DerSimonian-Laird random effects model,24 that recognizes and anchors studies as a sample of all potential studies, and incorporates an additional between-study component to the estimate of variability.25 We calculated the I2 statistic for each analysis as a measure of the proportion of the overall variation that is attributable to between-study heterogeneity.26 To investigate the association between statin treatment and risk of mortality or stroke, we conducted a weighted meta-regression for study characteristics using the unrestricted maximum likelihood model.27 Our specific covariates include: statin, proportion female, proportion history of coronary heart disease (CHD), proportion smokers, proportion hypertension, proportion diabetics, age, statin dosage, absolute cholesterol changes, and length of follow-up. We chose these co-variates as we believed they are likely to influence trial outcomes beyond chance. Study characteristics were tested for independent association with treatment effect for all-cause mortality and all-stroke outcomes. This potential association was further investigated by adjusting for type of statin used in the treatment group. Forest plots are displayed for each all-statins analysis, showing individual study proportions with 95% CIs, and the overall DerSimonian-Laird pooled estimate. Analyses were conducted using STATA (Version 9, StataCorp, College Station, Tex; www.stata.com) and Comprehensive Meta-Analysis (Version 2, Biostat, Inc., Englewood, NJ).

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Results 

Our literature search identified 1003 relevant abstracts of full text articles. Of these, 162 full text articles reported on 51 clinical trials addressing clinical outcomes, 42 of those addressed the outcomes of interest for this study. There was near-perfect agreement between reviewers on inclusion of the 42 studies enrolling a total of 121,285 patients (Phi=0.88) (Figure 1).4, 5, 7, 9, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65

Table 1 displays the study characteristics. The median sample size of the included studies is 902 (interquartile range [IQR] 361-4349). We included 8 studies assessing atorvastatin (total n=23,724),9, 34, 36, 39, 45, 49, 58, 60 6 studies assessing simvastatin (total n=26,146),4, 7, 29, 37, 53, 59 5 studies assessing fluvastatin (total n=5191),42, 43, 46, 52, 55 18 studies assessing pravastatin (total n=57,573),5, 28, 30, 31, 32, 35, 40, 44, 47, 48, 50, 51, 54, 56, 57, 62, 63, 65 one of which stopped early,31 4 studies assessing lovastatin (n=8102),33, 38, 41, 61 and one evaluating any statin.64 No rosuvastatin trials met our inclusion criteria. Only one trial assessed the impact of statins on secondary prevention of stroke (RR 0.85, 95% CI, 0.73-0.99, P=.04).34

Table 1. Study Characteristics and Primary Outcomes
Study IdentifierStatinn Treatment/ControlAverage DosageFollow-up (Years)Coronary Heart DiseaseAverage Age (Years)Women (%)Diabetes (%)Hypertension (%)Smoker (%)LDL Change Between Groups (%)All-Cause Mortality Treatment ControlStroke Treatment/Control
SPARCLAtorvastatin23652366804.90.0006340.416.761.819.1−0.410216211265311
4DAtorvastatin619636255.00.2946646.1100NA8.6−0.1522973205944
ASCOT-LLAAtorvastatin51685137103.30.0006318.824.610032.8−0.27618521289121
CARDSAtorvastatin14281410103.90.0006232.010083.822.2−0.33761822139
MohlerAtorvastatin24011410 to 801.00.0006822.917.5NA40.4−0.4305120
StoneAtorvastatin96103801.01.00021-8512.616.172.469.4−0.2741011
ALLIANCEAtorvastatin12171225354.31.0006117.822.1NA19.5−0.1101211273539
GREACEAtorvastatin800800453.01.0005921.519.642.9NA−0.4042340917
4SSimvastatin22212223255.41.0005818.64.526.025.6−0.3601822564774
CISSimvastatin129125402.31.0004900084.3−0.3501400
HPSSimvastatin10,26910,267405.00.6526424.719.041.214.2−0.20613281507452591
SCATSimvastatin230230252.01.0006110.910.935.215.0−0.34013647
MAASSimvastatin193188204.01.0005511.80NA23.9−0.31741112
Petronio ASimvastatin3635201.01.0006225.4070.446.5−0.1500100
ALERTFluvastatin1050105240 to 605.10.0705034.018.874.918.5−0.3201431385945
BCAPFluvastatin395398403.00.0436254.53.212.230.8−0.230NANA35
FLORIDAFluvastatin265275801.01.0006117.011.025.0NA−0.30071121
O’RourkeFluvastatin5227401.01.0005215.2079.80−0.2532010
LIPSFluvastatin844833803.91.0006016.212.138.626.6−0.380364921
CAIUSPravastatin151154403.00.0005546.9NANA24.0−0.2401000
CAREPravastatin20812078404.81.0005914.014.542.521.0−0.2801801965276
KAPSPravastatin224223403.00.0765702.533.126.2−0.2893424
LIPIDPravastatin45124502406.11.0006216.88.741.79.6−0.250498633169204
PHYLLISPravastatin254254402.60.0005859.6NA10016.1−0.2011010
PLAC IPravastatin206202403.01.0005862.01.022.38.1−0.2904602
PMSGPravastatin530532301.50.4045523.3047.528.7−0.2600303
PREVEND ITPravastatin433431404.00.0195135.12.600039.9−0.219131274
PROSPERPravastatin28912913403.20.2697545.110.761.926.8−0.322298306135131
REGRESSPravastatin450434402.01.0005600.127.828.0−0.2675735
WOSCOPSPravastatin33023293404.90.0805501.215.744.1−0.2601061354651
ALLHAT-LLTPravastatin51705185306.00.1426648.835.110023.2−0.139631641209231
GISSIPravastatin21382133202.01.0004713.713.636.511.8−0.16672882019
PCSPravastatin5466105.01.000608.317.559.267.5−0.1195334
ATHEROMAPravastatin182179153.01.0005913.618.842.0NA−0.1861254
Makuuchi HPravastatin152151155.01.0005920.433.351.541.9−0.14461115
KLISPravastatin27121637Mixed5.10.00058023.643.839.8NANANA4734
MEGAPravastatin38663966105.30.0005868.420.842.020.6−0.15055795062
ACAPSLovastatin460459303.00.0006248.42.328.712.0−0.2091905
MARSLovastatin123124732.21.000589.3045.680.0−0.3712101
CCAITLovastatin165166502.01.0005218.713.937.527.2−0.2742210
AFCAPSLovastatin33043301205.20.0005815.16.021.912.4−0.265NANA1417
MUSASHI-AMIMixed237244Mixed2.01.0006321.229.659.953.7−0.170NANA32

SPARCL=Stroke Prevention by Aggressive Reduction in Cholesterol Levels; 4D=Deutsche Diabetes Dialyse Studie; ASCOT-LLA=Anglo-Scandinavian Cardiac Outcomes Study Trial Lipid-Lowering Arm; CARDS=Collaborative Atorvastatin Diabetes Study; ALLIANCE=Aggressive Lipid-Lowering Inititation Abates New Cardiac Events; GREACE=Greek Atorvastatin and Coronary Heart Disease Evaluation Study; 4S=Scandinavian Simvastatin Survival Study; CIS=The multicenter Coronary Intervention Study; HPS=Heart Protection Study; SCAT=Simvastatin/Enalapril Coronary Atherosclerosis Trial; MAAS=Multicentre Anti-Atheroma Study; ALERT=Assessment of Lescol in Renal Transplant; BCAP=Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study; FLORIDA=Fluvastatin On Risk Diminishment after Acute myocardial infarction; LIPS=Lescol Intervention Prevention Study; CAIUS=Carotid Atherosclerosis Italian Ultrasound Study; CARE=Cholesterol And Recurrent Events; KAPS=Kuopio Atherosclerosis Prevention Study; LIPID=Long-term Intervention with Pravastatin in Ischemic Disease; PHYLLIS=Plaque Hypertension Lipid-Lowering Italian Study; PLAC-I=Pravastatin Limitation of Atherosclerosis in the Coronary arteries; PREVEND IT=Prevention of Renal and Vascular Endstage Disease Intervention Trial; PROSPER=Pravastatin in elderly individuals at risk of vascular disease; REGRESS=Regression Growth Evaluation Statin Study; WOSCOPS=West of Scotland Coronary Prevention Study; ALLHAT-LLT=Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial – Lipid-Lowering Trial; GISSI=Gruppo Italiano per lo Studio dela Sopravvivenza nell’Infarcto Miocardico; PCS=Prevention of Coronary Sclerosis; ATHEROMA=HMG-CoA Reductase inhibitor to Evaluate Retardation of Obstructive Multiple Atheroma; KLIS=Kyushu Lipid Intervention Study; MEGA=Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; ACAPS=Asymptomatic Carotid Artery Progression Study; MARS=Monitored Atherosclerosis Regression Study; CCAIT=Canadian Coronary Atherosclerosis Intervention Trial; AFCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; MUSASHI-AMI=Effects of Early Statin Treatment on Symptomatic Heart Failure and Ischemic Events after Acute Myocardial Infarction in Japanese; LDL=low-density lipoprotein.

Five studies assessed usual care as a control.31, 32, 36, 45, 64 Studies evaluating usual care were not significantly different from studies evaluating placebo controls in all-cause mortality (P=.57) or all-stroke (P=.45).

Impact of Statin Therapy on Primary Outcomes 

Table 1 presents the outcomes from the individual trials. We pooled a total of 40 studies assessing 116,080 patients for all-cause mortality.4, 5, 7, 9, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 As displayed in Figure 2, the pooled RR of all-statin therapy is 0.88 (95% CI 0.83-0.93, I2=25%, Heterogeneity P = .07). Using meta-regression, absolute LDL change was the only significant predictor of effect size (RR 1.003, 95% CI, 1.0006-1.006, P=.02).

We pooled a total of 42 studies assessing the impact of statin therapy on all strokes (total n=121,285; Figure 3).4, 5, 7, 9, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65 We found a pooled RR of all-statin therapy of 0.84 (95% CI, 0.79-0.91, I2 = 0%, Heterogeneity P=.49). Using meta-regression, we were unable to identify within-class differences among the differing statins.

Secondary Outcomes 

Figure 4 displays a forest plot of the pooled secondary outcomes. Seventeen trials evaluated statins on cardiovascular deaths (total n=57,599, RR 0.81, 95% CI, 0.74-0.90, I2=21%, Heterogeneity P=.21).4, 5, 28, 30, 31, 32, 33, 34, 35, 37, 41, 46, 48, 51, 60, 63, 64 Eleven trials evaluated nonhemorrhagic cerebrovascular events (total n=58,604, RR 0.81, 95% CI, 0.69-0.94, I2=49%, Heterogeneity P=.03).4, 5, 7, 28, 30, 33, 34, 47, 51, 60, 65 Eleven trials reported hemorrhagic stroke incidence (total n=54,334, RR 0.94, 95% CI, 0.68-1.30, I2=47%, Heterogeneity P=.05).4, 5, 7, 28, 30, 33, 34, 47, 51, 52, 60 Twenty-one trials reported on fatal strokes (total n=82,278, RR 0.99, 95% CI, 0.80-1.21, I2=28%, Heterogeneity P=.23).4, 5, 7, 28, 30, 31, 32, 33, 34, 39, 42, 43, 46, 47, 49, 52, 54, 55, 56, 57, 60

Meta-Regression 

Our meta-regression technique aimed to evaluate the effects of a priori identified covariates. These included: specific within-class effects, underlying conditions and patient characteristics, dosage, lipid changes, and follow-up. Only absolute LDL changes predicted marked effects. We found that every unit increase in LDL increased mortality risk by 0.3% (RR 1.003, 95% CI, 1.0005-1.006, P=.02). With the exception of absolute LDL changes, we were unable to predict the influence of any covariate using multivariate regression (Table 2).

Table 2. Meta-Regression Results
VariableAll-Cause MortalityStroke
UnivariateMultivariate⁎UnivariateMultivariate⁎
β†P Valueβ†P Valueβ†P Valueβ†P Value
Statin‡
Atorvastatin0.95.17 0.641.33
Lovastatin−0.194.71 −0.538.30
Fluvastatin0.562.30 0.744.08
Simvastatin−0.452.36 −0.016.97
Pravastatin−0.165.66 −0.371.28
% Female0.514.600.203.83−0.577.54−0.635.49
% CHD−0.201.620.085.850.048.900.118.78
% Smoke−0.610.50−0.172.850.363.680.716.41
Age0.019.64−0.018.70−0.006.88−0.044.30
% Hypertension1.218.101.229.110.382.630.467.56
% Diabetes0.626.64−0.204.890.508.64−0.039.97
Absolute LDL change0.003.020.156.820.303.44−0.038.29
Lifestyle
Intervention§0.315.410.193.620.334.350.260.46
Follow-up−0.091.56−0.048.76−0.142.31−0.105.44

CHD=coronary heart disease; LDL=low-density lipoprotein.

⁎Values adjusted for type of statin.

†Beta for log RR.

‡Effect of individual statin compared with all others.

§Includes dietary changes or exercise.

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Discussion 

We examined the impact of statin therapy on major clinical events and found that statins play an important role in preventing all-cause mortality and certain types of strokes. The role of statins in stroke prevention is not yet fully elucidated, and the safety of statins in hemorrhagic stroke incidence remains a concern. Our analysis represents the most comprehensive meta-analysis to date of statin therapy for stroke.

Approximately 15% of all strokes are heralded by a transient ischemic attack, and those patients who have a transient ischemic attack have a 10-year stroke risk of 19% and a combined 10-year stroke, myocardial infarction, or vascular death risk of approximately 43%.1 The recent Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial demonstrated that high-dose atorvastatin reduced the risk of subsequent stroke in patients with transient ischemic attack (TIA) or stroke, and the absence of coronary artery disease.34 Despite this emerging evidence for statins in stroke prevention, there remain several important questions. The SPARCL data, for instance, conflict with earlier subgroup data from the Heart Protection Study that suggested no stroke risk reduction in patients with pre-existing cerebrovascular disease.10 Possible reasons have been reviewed elsewhere, but include that the SPARCL inclusion criteria had a higher incidence of annual recurrence stroke than other trials that might have included cerebrovascular accident patients—but not as the target inclusion group.66 The SPARCL study is somewhat unique, as enrolled patients had experienced a stroke or TIA but had no evidence of coronary heart disease. Patients in the SPARCL study randomized to high-dose atorvastatin had significantly lower rates of stroke (RR 0.85, 95% CI, 0.73-0.99), stroke or TIA (RR 0.77, 95% CI 0.67-0.88), and coronary events (0.65, 95% CI, 0.49-0.87) than placebo-treated patients. This study did, however, find an increased risk of hemorrhagic strokes (RR 1.25, 95% CI, 1.06-1.47), a finding that was not resolved through our meta-analysis of 54,334 patients (RR 0.94, 95% CI, 0.68-1.30).

There are several important strengths to our meta-analysis that should be considered when interpreting this study. We used extensive searching of electronic databases to identify studies. In order to reduce bias, we conducted our searches independently, in duplicate. We extensively searched the bibliographies of published trials, reviews, and health technology assessments in order to identify unpublished or obscure papers. We contacted the authors of individual trials and also the authors of previous meta-analyses to clarify conflicting outcomes and study reports. Finally, we used methodologically advanced approaches to pool and conduct sensitivity analyses across a priori defined covariates.

There also are several limitations to consider when interpreting our meta-analysis. We included placebo and standard care trials in our analysis. We additionally collected all head-to-head trials, but these were consistently dose-ranging studies rather than superiority. We examined 6 major clinical outcomes. It is possible that other outcomes would yield differing effects. Also, it is possible that we did not identify all studies that have been conducted. However, our searches were thorough and there was no indication of asymmetry on funnel plots of the pooled outcomes (data not shown). We conducted meta-regression to determine if individual statins yielded differing effect estimates. Indirect comparisons provide compelling, but ultimately weak, comparisons.67 It is possible that head-to-head trials would yield different outcomes. We were able to display a relationship between absolute LDL change and all-cause mortality, but unable to display this relationship when examining stroke outcomes. Finally, we did not examine risk profiles of the individual statins. A recent meta-analysis of harms associated with statins found that serious adverse events are rare and that differing harm effects might exist across statins, with atorvastatin presenting the greatest likelihood of adverse events and fluvastatin the least—other statins all had similar risk profiles.68

We were unable to display that the cholesterol-lowering effects of statins have a protective role in strokes, likely due to restricted variance of the independent variables across trials. However, it may be possible that the pleiotropic effect of statins is more protective in ischemic stroke than LDL reduction alone. Statins have been shown to have an anti-inflammatory effect via suppression of T-cell activation, inhibition of proinflammatory cyctokines, and reduction in C-reactive protein (an independent risk factor for the development of ischemic strokes).69 Furthermore, statins may improve endothelial dysfunction by increasing nitric oxide bioavailability and lead to plaque stabilization and decreased plaque thrombogenicity by decreasing macrophage number, limiting monocyte adhesion to endothelium, and reducing the expression of tissue factor, adhesion molecules, and matrix metalloproteinases within plaques.15, 69

Given the global burden of cerebrovascular disease, impacting almost all population groups, the potential benefits of statins cannot be overlooked. Most clinical trials evaluating statin effectiveness occur as primary prevention trials. With the exception of atorvastatin use in the SPARCL trial, we do not know the role of specific statins in secondary prevention. What appears to be of prime concern now is the appropriate use of statin therapy from a public health perspective. As policymakers aim to develop guidelines on widespread use of statins, the relative effectiveness of statins is important in order to determine what statins health ministries should be supplying. There is a pressing need for direct evidence, from head-to-head trials, to determine if individual statins provide differing protection from clinically important events.

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Author Disclosures 

This study was supported by Pfizer UK Ltd. Christopher O’Regan, MSc, is a salaried employee of Pfizer UK Ltd.

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Acknowledgments 

We thank Dr. Matthias Briel and Dr. Colin Baigent for detailed comments on their previous meta-analyses. We thank Dr. Gordon Guyatt for suggestions on the revised manuscript.

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PII: S0002-9343(07)00977-1

doi:10.1016/j.amjmed.2007.06.033

The American Journal of Medicine
Volume 121, Issue 1 , Pages 24-33, January 2008

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