CLINICAL RESEARCH STUDY

Statin Therapy in Stroke Prevention: A Meta-analysis

Involving 121,000 Patients
Christopher O’Regan, MSc,a Ping Wu, MBBS, MSc,a Paul Arora, MSc,b Dan Perri, BScPhm, MD,c
Edward J. Mills, MSc, PhDd
a
Department of Epidemiology, London School of Hygiene and Tropical Medicine, London, UK; bCentre for Global Health Research,
University of Toronto, Ontario, Canada; cDepartment of Medicine, McMaster University, Hamilton, Ontario, Canada; dDepartment of
Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.

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 nonhemor-
rhagic 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.
© 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, 24-33

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
Dr. Mills is supported by the Canadian Institutes of Health Research.
Requests 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.
E-mail address: millsej@mcmaster.ca
Epidemiologic studies have not demonstrated a clear rela-
tionship between the risk of ischemic stroke and dyslipide-
mia.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 reduc-
tase inhibitors (statins) with a reduction in stroke risk.4-13
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

0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjmed.2007.06.033
O’Regan et al Statins for Stroke: A Meta-Analysis 25

suggest a role for statins in stroke prevention independent of tematic reviews11-14,16-20 and health technology assess-
coronary artery disease risk reduction or serum lipid levels. ments.21 We also contacted the authors of all trials for study
Statins have been associated with a variety of pleiotropic ef- clarifications, where required, and the authors of the only
fects, including atherosclerotic plaque stabilization, decreased individual-patient data meta-analysis of statins for stroke,
inflammation, improvement in endothelial function, and al- which included 14 trials.20 Searches were not limited by
15
tered thrombogenicity. language, sex, or age.
Before entering an exciting era
of statin stroke prevention, it is
CLINICAL SIGNIFICANCE Study Selection
important to determine if, from the Two investigators (EM, PW) work-
totality of evidence to date, all st- ● In a comprehensive meta-analysis, st- ing independently, in duplicate,
atins have a role in primary and atins effectively reduced risk of all- scanned all abstracts and obtained
secondary stroke prevention, and cause death and of nonhemorrhagic the full text reports of records that
if any benefits are dose dependent. indicated or suggested that the study
stroke.
Using a systematic review of the was a randomized trial evaluating
literature and meta-analytic tech- ● Every unit increase in low-density li- statin therapy on the outcomes of
niques, we aimed to quantify the poprotein (LDL) increased relative mor- interest. After obtaining full reports
effects of statin therapy on both tality risk by 0.3%, but neither LDL of the candidate trials (either in full
primary and secondary stroke pre- change nor any other covariate affected peer-reviewed publication or press
vention, and any associated mor- stroke risk. article), the same reviewers inde-
tality benefit. We further sought to pendently assessed eligibility from
determine differences in stroke ● Few head-to-head trials exist to guide
full text articles.
risk reduction among a variety of practice about the relative benefits of
statins, dosing strategies, and specific statins. Data Collection
types of stroke. The same 2 reviewers conducted
● Other known effects of statins might be
more important than LDL reduction in data extraction independently us-
METHODS protecting against ischemic stroke. ing a standardized prepiloted
form. Reviewers collected infor-
Eligibility Criteria ● Despite the compelling evidence of pri- mation about the statin and type of
We included any randomized trial mary therapeutic protection for strokes, interventions tested, the popula-
of atorvastatin, fluvastatin, lova- secondary prevention trials are desper- tion studied (age, sex, underlying
statin, pravastatin, rosuvastatin, ately needed. conditions), the treatment effect
and simvastatin. We included ran- on specified outcomes, change in
domized trials of any duration. LDL, high density lipoprotein,
Studies had to compare a statin to and total cholesterol, and the
placebo or no treatment, and report on any of the following length of follow-up. Study evaluation included general
clinically important cardiovascular outcomes: all-cause methodological quality features. We entered the data into an
mortality, all-stroke incidence, fatal strokes, hemorrhagic, electronic database such that duplicate entries existed for
or ischemic strokes. We excluded studies reporting only on each study; when the 2 entries did not match, we resolved
surrogate outcomes (eg, LDL and high-density lipoprotein differences through discussion and consensus.
[HDL] levels).
Data Analysis
Search Strategy In order to assess inter-rater reliability on inclusion of articles,
In consultation with a medical librarian, we established a we calculated the Phi statistic, which provides a measure of
search strategy (available from corresponding author on inter-observer agreement independent of chance.22 We calcu-
request). We searched independently, in duplicate, the fol- lated the relative risk (RR) and appropriate 95% confidence
lowing 10 databases (from inception to December 2006): intervals (CIs) of outcomes according to the number of events
MEDLINE, EMBASE (Exerpta Medica), Cochrane Central reported in the original studies or sub-studies. In the case of an
Register of Controlled Trials (CENTRAL), Allied and individual-patient data meta-analysis of 14 trials, we included
Complementary Medicine Database (AMED), Cumulative outcomes as reported by the meta-analysis, in correspondence
Index to Nursing and Allied Health Literature (CINAHL), with all the study’s authors. In the event of zero outcome
TOXNET, Development and Reproductive Toxicology, events in one arm of a trial, we used the Haldane method and
Hazardous Substances Databank, Psych-info, and Web of added 0.5 to each arm.23 We pooled studies as an analysis of
Science, databases that included the full text of journals all-statins combined using the DerSimonian-Laird random ef-
(OVID, ScienceDirect, and Ingenta, including articles in fects model,24 that recognizes and anchors studies as a sample
full text from approximately 1700 journals since 1993). In of all potential studies, and incorporates an additional between-
addition, we searched the bibliographies of published sys- study component to the estimate of variability.25 We calculated
26 The American Journal of Medicine, Vol 121, No 1, January 2008

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 covari-
ates 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, Stata-
Corp, College Station, Tex; www.stata.com) and Comprehen-
sive Meta-Analysis (Version 2, Biostat, Inc., Englewood, NJ).

RESULTS Figure 1 Flowchart of included studies.

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).4,5,7,9,28-65
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 sim-
vastatin (total n ⫽ 26,146),4,7,29,37,53,59 5 studies assessing fluva-
statin (total n ⫽ 5191),42,43,46,52,55 18 studies assessing prava-
statin (total n ⫽ 57,573),5,28,30-32,35,40,44,47,48,50,51,54,56,57,62,63,65
one of which stopped early,31 4 studies assessing lovastatin
(n ⫽ 8102),33,38,41,61 and one evaluating any statin.64 No rosu-
vastatin 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
Five studies assessed usual care as a control.31,32,36,45,64
Studies evaluating usual care were not significantly differ-
ent 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.4,5,7,9,28-41,43-64 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-regres-
sion, absolute LDL change was the only significant predic-
tor 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).4,5,7,9,28-65 We found a pooled RR of all-statin
therapy of 0.84 (95% CI, 0.79-0.91, I2 ⫽ 0%, Heteroge-
neity 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 out-
comes. 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).4,5,28,30-35,37,41,46,48,51,60,63,64
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).4,5,7,28,30-34,39,42,43,46,47,49,52,54-57,60
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 char-
acteristics, dosage, lipid changes, and follow-up. Only ab-
 O’Regan et al
Table 1 Study Characteristics and Primary Outcomes
All-Cause
Coronary Average LDL Change Mortality Stroke

Statins for Stroke: A Meta-Analysis

Study Average Follow-up Heart Age Women Diabetes Hypertension Smoker Between Treatment Treatment/
Identifier Statin n Treatment/Control Dosage (Years) Disease (Years) (%) (%) (%) (%) Groups (%) Control Control

SPARCL Atorvastatin 2365 2366 80 4.9 0.000 63 40.4 16.7 61.8 19.1 ⫺0.410 216 211 265 311
4D Atorvastatin 619 636 25 5.0 0.294 66 46.1 100 NA 8.6 ⫺0.152 297 320 59 44
ASCOT-LLA Atorvastatin 5168 5137 10 3.3 0.000 63 18.8 24.6 100 32.8 ⫺0.276 185 212 89 121
CARDS Atorvastatin 1428 1410 10 3.9 0.000 62 32.0 100 83.8 22.2 ⫺0.337 61 82 21 39
Mohler Atorvastatin 240 114 10 to 80 1.0 0.000 68 22.9 17.5 NA 40.4 ⫺0.430 5 1 2 0
Stone Atorvastatin 96 103 80 1.0 1.000 21-85 12.6 16.1 72.4 69.4 ⫺0.274 1 0 1 1
ALLIANCE Atorvastatin 1217 1225 35 4.3 1.000 61 17.8 22.1 NA 19.5 ⫺0.110 121 127 35 39
GREACE Atorvastatin 800 800 45 3.0 1.000 59 21.5 19.6 42.9 NA ⫺0.404 23 40 9 17
4S Simvastatin 2221 2223 25 5.4 1.000 58 18.6 4.5 26.0 25.6 ⫺0.360 182 256 47 74
CIS Simvastatin 129 125 40 2.3 1.000 49 0 0 0 84.3 ⫺0.350 1 4 0 0
HPS Simvastatin 10,269 10,267 40 5.0 0.652 64 24.7 19.0 41.2 14.2 ⫺0.206 1328 1507 452 591
SCAT Simvastatin 230 230 25 2.0 1.000 61 10.9 10.9 35.2 15.0 ⫺0.340 13 6 4 7
MAAS Simvastatin 193 188 20 4.0 1.000 55 11.8 0 NA 23.9 ⫺0.317 4 11 1 2
Petronio A Simvastatin 36 35 20 1.0 1.000 62 25.4 0 70.4 46.5 ⫺0.150 0 1 0 0
ALERT Fluvastatin 1050 1052 40 to 60 5.1 0.070 50 34.0 18.8 74.9 18.5 ⫺0.320 143 138 59 45
BCAP Fluvastatin 395 398 40 3.0 0.043 62 54.5 3.2 12.2 30.8 ⫺0.230 NA NA 3 5
FLORIDA Fluvastatin 265 275 80 1.0 1.000 61 17.0 11.0 25.0 NA ⫺0.300 7 11 2 1
O’Rourke Fluvastatin 52 27 40 1.0 1.000 52 15.2 0 79.8 0 ⫺0.253 2 0 1 0
LIPS Fluvastatin 844 833 80 3.9 1.000 60 16.2 12.1 38.6 26.6 ⫺0.380 36 49 2 1
CAIUS Pravastatin 151 154 40 3.0 0.000 55 46.9 NA NA 24.0 ⫺0.240 1 0 0 0
CARE Pravastatin 2081 2078 40 4.8 1.000 59 14.0 14.5 42.5 21.0 ⫺0.280 180 196 52 76
KAPS Pravastatin 224 223 40 3.0 0.076 57 0 2.5 33.1 26.2 ⫺0.289 3 4 2 4
LIPID Pravastatin 4512 4502 40 6.1 1.000 62 16.8 8.7 41.7 9.6 ⫺0.250 498 633 169 204
PHYLLIS Pravastatin 254 254 40 2.6 0.000 58 59.6 NA 100 16.1 ⫺0.201 1 0 1 0
PLAC I Pravastatin 206 202 40 3.0 1.000 58 62.0 1.0 22.3 8.1 ⫺0.290 4 6 0 2
PMSG Pravastatin 530 532 30 1.5 0.404 55 23.3 0 47.5 28.7 ⫺0.260 0 3 0 3
PREVEND IT Pravastatin 433 431 40 4.0 0.019 51 35.1 2.6 000 39.9 ⫺0.219 13 12 7 4
PROSPER Pravastatin 2891 2913 40 3.2 0.269 75 45.1 10.7 61.9 26.8 ⫺0.322 298 306 135 131
REGRESS Pravastatin 450 434 40 2.0 1.000 56 0 0.1 27.8 28.0 ⫺0.267 5 7 3 5
WOSCOPS Pravastatin 3302 3293 40 4.9 0.080 55 0 1.2 15.7 44.1 ⫺0.260 106 135 46 51
ALLHAT-LLT Pravastatin 5170 5185 30 6.0 0.142 66 48.8 35.1 100 23.2 ⫺0.139 631 641 209 231
GISSI Pravastatin 2138 2133 20 2.0 1.000 47 13.7 13.6 36.5 11.8 ⫺0.166 72 88 20 19
PCS Pravastatin 54 66 10 5.0 1.000 60 8.3 17.5 59.2 67.5 ⫺0.119 5 3 3 4
ATHEROMA Pravastatin 182 179 15 3.0 1.000 59 13.6 18.8 42.0 NA ⫺0.186 1 2 5 4
Makuuchi H Pravastatin 152 151 15 5.0 1.000 59 20.4 33.3 51.5 41.9 ⫺0.144 6 11 1 5
KLIS Pravastatin 2712 1637 Mixed 5.1 0.000 58 0 23.6 43.8 39.8 NA NA NA 47 34
MEGA Pravastatin 3866 3966 10 5.3 0.000 58 68.4 20.8 42.0 20.6 ⫺0.150 55 79 50 62
ACAPS Lovastatin 460 459 30 3.0 0.000 62 48.4 2.3 28.7 12.0 ⫺0.209 1 9 0 5
MARS Lovastatin 123 124 73 2.2 1.000 58 9.3 0 45.6 80.0 ⫺0.371 2 1 0 1
CCAIT Lovastatin 165 166 50 2.0 1.000 52 18.7 13.9 37.5 27.2 ⫺0.274 2 2 1 0

27
28 The American Journal of Medicine, Vol 121, No 1, January 2008

solute LDL changes predicted marked effects. We found

4S ⫽ Scandinavian Simvastatin Survival Study; CIS ⫽ The multicenter Coronary Intervention Study; HPS ⫽ Heart Protection Study; SCAT ⫽ Simvastatin/Enalapril Coronary Atherosclerosis Trial;
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;

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;

Carotid Artery Progression Study; MARS ⫽ Monitored Atherosclerosis Regression Study; CCAIT ⫽ Canadian Coronary Atherosclerosis Intervention Trial; AFCAPS ⫽ Air Force/Texas Coronary Atherosclerosis
MAAS ⫽ Multicentre Anti-Atheroma Study; ALERT ⫽ Assessment of Lescol in Renal Transplant; BCAP ⫽ Beta-blocker Cholesterol-lowering Asymptomatic Plaque Study; FLORIDA ⫽ Fluvastatin On Risk Diminish-
ment after Acute myocardial infarction; LIPS ⫽ Lescol Intervention Prevention Study; CAIUS ⫽ Carotid Atherosclerosis Italian Ultrasound Study; CARE ⫽ Cholesterol And Recurrent Events; KAPS ⫽ Kuopio

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 –

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
Atherosclerosis Prevention Study; LIPID ⫽ Long-term Intervention with Pravastatin in Ischemic Disease; PHYLLIS ⫽ Plaque Hypertension Lipid-Lowering Italian Study; PLAC-I ⫽ Pravastatin Limitation of

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
17
2
Treatment/
that every unit increase in LDL increased mortality risk by

Control
Stroke 0.3% (RR 1.003, 95% CI, 1.0005-1.006, P ⫽ .02). With the

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.
14
3
exception of absolute LDL changes, we were unable to
predict the influence of any covariate using multivariate
NA regression (Table 2).
NA
Treatment
All-Cause
Mortality

Control

NA
NA

DISCUSSION
We examined the impact of statin therapy on major clinical
LDL Change

Groups (%)

events and found that statins play an important role in

Between

⫺0.265
⫺0.170

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
Smoker

incidence remains a concern. Our analysis represents the

12.4
53.7
(%)

most comprehensive meta-analysis to date of statin therapy

for stroke.
Approximately 15% of all strokes are heralded by a
Hypertension

transient ischemic attack, and those patients who have a

transient ischemic attack have a 10-year stroke risk of 19%
21.9
59.9
(%)

and a combined 10-year stroke, myocardial infarction, or

vascular death risk of approximately 43%.1 The recent
Diabetes

Stroke Prevention by Aggressive Reduction in Cholesterol

6.0
29.6
(%)

Levels (SPARCL) trial demonstrated that high-dose atorva-

statin reduced the risk of subsequent stroke in patients with
transient ischemic attack (TIA) or stroke, and the absence of
Women

15.1
21.2

coronary artery disease.34 Despite this emerging evidence

(%)

for statins in stroke prevention, there remain several impor-

tant questions. The SPARCL data, for instance, conflict
Average

(Years)

with earlier subgroup data from the Heart Protection Study

Age

58
63

that suggested no stroke risk reduction in patients with

pre-existing cerebrovascular disease.10 Possible reasons
Coronary

have been reviewed elsewhere, but include that the

Disease

0.000
1.000
Heart

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
Follow-up

inclusion group.66 The SPARCL study is somewhat unique,

(Years)

5.2
2.0

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
Average
Dosage

Mixed

significantly lower rates of stroke (RR 0.85, 95% CI, 0.73-

20

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-
n Treatment/Control

treated patients. This study did, however, find an increased

3301
244

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).
3304
237

There are several important strengths to our meta-anal-

ysis that should be considered when interpreting this study.
We used extensive searching of electronic databases to
Lovastatin
Mixed
Continued

identify studies. In order to reduce bias, we conducted our

Statin

searches independently, in duplicate. We extensively

searched the bibliographies of published trials, reviews, and
health technology assessments in order to identify unpub-
MUSASHI-AMI
Table 1

lished or obscure papers. We contacted the authors of indi-

Identifier

AFCAPS

vidual trials and also the authors of previous meta-analyses

Study

to clarify conflicting outcomes and study reports. Finally, we

O’Regan et al Statins for Stroke: A Meta-Analysis 29

Figure 2 Meta-analysis of all-cause mortality.

30 The American Journal of Medicine, Vol 121, No 1, January 2008

Figure 3 Meta-analysis of all strokes.

O’Regan et al Statins for Stroke: A Meta-Analysis 31

shown). We conducted meta-regression to determine if in-

Figure 4 Secondary outcomes.
used methodologically advanced approaches to pool and con-
duct sensitivity analyses across a priori defined covariates.
There also are several limitations to consider when in-
terpreting our meta-analysis. We included placebo and stan-
dard care trials in our analysis. We additionally collected all
head-to-head trials, but these were consistently dose-rang-
ing 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
dividual statins yielded differing effect estimates. Indirect
comparisons provide compelling, but ultimately weak, com-
parisons.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 associ-
ated 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 ad-
verse 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 devel-
opment of ischemic strokes).69 Furthermore, statins may
improve endothelial dysfunction by increasing nitric oxide
bioavailability and lead to plaque stabilization and de-
creased plaque thrombogenicity by decreasing macrophage
number, limiting monocyte adhesion to endothelium, and

Table 2 Meta-Regression Results

All-Cause Mortality Stroke

Univariate Multivariate* Univariate Multivariate*

Variable ␤† P Value ␤† P Value ␤† P Value ␤† P Value

Statin‡
Atorvastatin 0.95 .17 0.641 .33
Lovastatin ⫺0.194 .71 ⫺0.538 .30
Fluvastatin 0.562 .30 0.744 .08
Simvastatin ⫺0.452 .36 ⫺0.016 .97
Pravastatin ⫺0.165 .66 ⫺0.371 .28
% Female 0.514 .60 0.203 .83 ⫺0.577 .54 ⫺0.635 .49
% CHD ⫺0.201 .62 0.085 .85 0.048 .90 0.118 .78
% Smoke ⫺0.610 .50 ⫺0.172 .85 0.363 .68 0.716 .41
Age 0.019 .64 ⫺0.018 .70 ⫺0.006 .88 ⫺0.044 .30
% Hypertension 1.218 .10 1.229 .11 0.382 .63 0.467 .56
% Diabetes 0.626 .64 ⫺0.204 .89 0.508 .64 ⫺0.039 .97
Absolute LDL change 0.003 .02 0.156 .82 0.303 .44 ⫺0.038 .29
Lifestyle
Intervention§ 0.315 .41 0.193 .62 0.334 .35 0.260 .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.
32
reducing the expression of tissue factor, adhesion mole-
cules, and matrix metalloproteinases within plaques.15,69
Given the global burden of cerebrovascular disease, im-
pacting almost all population groups, the potential benefits
of statins cannot be overlooked. Most clinical trials evalu-
ating 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 per-
spective. As policymakers aim to develop guidelines on
widespread use of statins, the relative effectiveness of st-
atins 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 clini-
cally important events.
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.
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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