International Journal of Cardiology 138 (2010) 25 31

www.elsevier.com/locate/ijcard

Impact of gender in primary prevention of coronary heart disease

with statin therapy: A meta-analysis
Mario Petretta , Pierluigi Costanzo, Pasquale Perrone-Filardi, Massimo Chiariello
Department of Clinical Medicine, Immunological and Cardiovascular Sciences, Federico II University, Via S. Pansini 5 Naples 80131, Italy
Received 8 July 2008; accepted 10 August 2008
Available online 14 September 2008

Abstract
Background: Evidence of lipid-lowering from clinical trials that included women is adequate to support their use in secondary prevention in
women with known coronary disease. However the role of statin therapy in primary prevention is still controversial, in particular for female
gender. The aim of our study is to perform a meta-analysis comparing by gender the cardiovascular outcomes related to statin therapy in
primary prevention.
Methods: We performed a meta-analysis including 8 randomized controlled trials (19,052 and 30,194 men, mean follow-up 3.9 years) that
assessed the cardiovascular outcomes related to statin therapy, including studies that provided sex-specific results. MEDLINE and the
Cochrane Database, were searched for articles published in English and other languages up to March 2008.
Results: Statins do not appear to have a beneficial effect on total mortality for both men and women in primary prevention over the 2.8- to
5.3 year study period (men: 95% Confidence Interval (CI) 0.831.04; comparison p = 0.22; women: 0.96; CI 0.811.13; p = 0.61). Statin
therapy reduced the risk of coronary heart disease (CHD) events in men (0.59; CI 0.480.74; p = 0.0001), however in women this risk
reduction was weakly significant (0.89 CI 0.791.00; p = 0.05) and disappeared when in sensitivity analysis, trials not entirely of primary
prevention were excluded (HPS, PROSPER) (0.95 CI 0.781.16; comparison p = 0.562).
Conclusions: Our study showed that statin therapy reduced the risk of CHD events in men without prior cardiovascular disease, but not in
women. Statins did not reduce the risk of total mortality both in men and women.
2008 Elsevier Ireland Ltd. All rights reserved.
Keywords: Statins; Primary prevention; Gender; Coronary heart disease

1. Introduction
The focus on cardiovascular risk treatment in women is
rising. Indeed, for women the risk of cardiovascular events is
lower than that of men at any given age and the onset of
cardiovascular disease in women lags about 10 years behind
men [1]. However, despite an overall reduction in the death
rate due to cardiovascular disease in the United States over
the last several decades, the rate of decline is less for women
than men [2]. The impression that women are relatively

Corresponding author. Tel.: +39 081 7462233; fax: +39 081 7462229.
E-mail address: petretta@unina.it (M. Petretta).
0167-5273/$ - see front matter 2008 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ijcard.2008.08.001

protected from cardiovascular events, until the menopausal

age, leads to a less aggressive approach to cardiovascular risk
factors and, mostly, to a less intense cholesterol management
than men. That could be one of the reasons of this gender
difference on mortality for cardiovascular disease [3,4].
Evidence of lipid-lowering from clinical trials that included women is adequate to support their use in secondary
prevention in women with known coronary disease. However
the role of lipid-lowering medications in primary prevention
is still controversial, indeed, current evidence fails to report a
clear reduction of total mortality or coronary heart disease
events and mortality [5].
That may also depend on the insufficient number of
women included in the trials as many did not include

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M. Petretta et al. / International Journal of Cardiology 138 (2010) 2531

adequate numbers of women to allow sex-specific analyses.

Previous systematic overviews did not report a comparison of
anti-cholesterolemic effect of statin therapy in primary
prevention between men and women. In addition, recently,
a large trial of statin treatment in primary prevention (MEGA)
[6], including more than 5000 women, showed that pravastatin in women with elevated cholesterol but no history
of cardiovascular disease provides a benefit similar to that
seen in men. Thus, performing a meta-analysis including also
this study would yield additional insight into the issue. The
aim of our study is to perform a meta-analysis comparing by
gender the cardiovascular outcomes related to statin therapy
in primary prevention.
2. Methods
2.1. Search strategy and data extraction
This meta-analysis is reported following the QUOROM
statement [7]. Inclusion criteria for a study to be included in
this overview were: randomized clinical trials of patients
without known cardiovascular disease (primary prevention);
available data on women and the effect of lipid-lowering drug
therapy was assessed for at least 1 clinical outcome (total
mortality, coronary heart disease (CHD) mortality, nonfatal
myocardial infarction, CHD events, revascularization procedures). CHD events are defined as CHD mortality, nonfatal
MI, unstable angina, or sudden cardiac death. We excluded
studies with the following characteristics: compared high
to low dose statins; pre-screened patients with ultrasound
for the presence of atherosclerosis; targeted patients with disease states that are not traditional cardiovascular risk factors
(e.g., dialysis or posttransplantation patients); examined only
changes in serum cholesterol concentration or angiographic
outcomes; did not report the proportion of study participants
receiving therapy as primary prevention.

MEDLINE, the Cochrane Database, and the Database

of Abstracts of Reviews of Effectiveness were searched for
articles published in English and other languages from January
2002 up to March 2008. Studies were identified through
PubMed searches of the MEDLINE database with the MeSH
headings hyperlipidemia, simvastatin, lovastatin, pravastatin, atorvastatin, fluvastatin, cardiovascular diseases, heart diseases, myocardial ischemia, and coronary
disease. We searched reference lists of the retrieved articles to
identify other eligible studies, and information from colleagues
was used to identify more recently published articles. For
eligible studies, each group of the controlled clinical trial was
classified according to whether or not the primary treatment
strategy used a statin in primary prevention. Some studies used
more than one drug in each treated group, but the agents were
generally applied in a stepped approach, and the first-line agent
was clearly identified.
Two reviewers independently selected trials using the
search strategy for relevance and inclusion or exclusion by
reading titles and abstracts of studies. The selected trials were
compared and any discrepancies were resolved by discussion
and consensus. Two reviewers, independently, read the
full text of retained studies and included trials that meet the
inclusion criteria. Articles finally selected for the review
were checked to avoid including data published in duplicate.
Data on the outcomes of total mortality, coronary heart disease (CHD) mortality, nonfatal myocardial infarction, CHD
events, revascularization procedures were extracted. We
evaluated quality score for each trial with Jadad et al. [8]
method (Table 1) and then we included it as a weight in metaanalysis. The initial search identified 848 articles, of those 8
were included according to all inclusion criteria (Fig. 1). The
randomized clinical trials included in our meta-analysis were:
Asymptomatic Carotid Artery Progression Study (ACAPS)
[9], Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS) [10], The Antihypertensive and

Table 1
Characteristics of included trials.
Trial

Women/Total
Population

Mean age

Lipid Entry
Criterion

Statin

Control
Treatment

Mean
Follow-up

Degree of
binding

Year

Jadad
score [8]

ACAPS

445/919

61,7

Lovastatin

Placebo

2,8

Double-blinded

1994

AFCAPS/
TEXCAPS

997/6605

63

Lovastatin

Placebo

5,3

Double-blinded

1998

ALLHAT
ASCOT
HPS
MEGA

5051/10355
1942/10305
1816/5963
5356/7832

NA
NA
NA
60

Pravastatin
Atorvastatin
Simvastatin
Pravastatin

Usual care
Placebo
Placebo
Diet

4,8
3.03
5
5,3

PROBE
Double-blinded
Double-blinded
PROBE

2002
2003
2003
2006

2
4
5
5

PROSPER
WOSCOPS

3000/5804
0/6595

75
55

LDL 130159 mg/dL with

other risk factors;
LDL 160189 mg/dL with
none or 1 risk factor
Total cholesterol, 180264 mg/dL;
LDL 130190 mg/dL;
and HDL b 47 mg/dL
LDL, 100189 mg/dL
Total cholesterol N 250 mg/dL
Total cholesterol N 135 mg/dL
Total cholesterol levels
ranged from 5.7 to 7.0 mmol/L
(N220 mg/dL
Total cholesterol N 180 mg/dL
Total cholesterol N 155 mg/dL

Pravastatin
Pravastatin

Placebo
Placebo

3,2
4,9

Double-blinded
Double-blinded

2002
1995

5
4

NA: Not Applicable; LDL: Low Density Lipoprotein; HDL: High Density Lipoprotein. PROBE: Prospective Randomized Open Blinded Endpoint.

M. Petretta et al. / International Journal of Cardiology 138 (2010) 2531

Fig. 1. Flow chart showing the progress through the stages of the metaanalysis. RCT: Randomized Controlled Trial.

27

Meta-analysis was re-analyzed excluding studies with a

Jadad score b 3 (ALLHAT) (MantelHaenszel methodology)
[21]. To evaluate potential publication bias, we performed a
rank correlation method proposed by Begg and Mazumdar
[22] and a test proposed by Egger based on a linear regression
approach [23].
We performed sensitivity analysis if studies appeared to be
outliers, assessing their influence on summary estimates by
including and excluding them. In particular, we focused our
sensitivity analysis on studies with a very greater population
(ALLHAT) [11] or with results different from the rest of the
studies, (ALLHAT) [11], or if they were not at all primary
prevention studies (HPS [13], PROSPER [15]). Moreover,
sensitivity analysis for ALLHAT [11] trial was performed
also because a smaller than expected differential in total
cholesterol was found between the treatment and usual care
groups (9.6%) and also, as said above, because of its poor
Jadad quality score (see Table 1).
3. Results

Lipid-Lowering Treatment to Prevent Heart Attack Trial

(ALLHAT-LLT) [11], Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) [12],
Heart Protection Study (HPS) [13], Primary prevention of
cardiovascular disease with pravastatin in Japan (MEGA)
[14], Pravastatin in elderly individuals at risk of vascular
disease (PROSPER) [15], West of Scotland Coronary
Prevention Study (WOSCOPS) [16].
2.2. Data analysis
Effects of randomized treatments were analysed with the
metan routine [17] (STATA Statacorp, version 10.0). To
avoid calculation problems associated with zero cells, 0.5
was added to all cells to calculate variances and SD [18].
Relative risks and 95% confidence intervals (CIs) for every
outcome were calculated separately for each trial, with
grouped data, in intention-to-treat analyses. Overall estimates
of effect were calculated with inverse-variance model [19].
We used this method, and not fixed effect model, because one
study (ALLHAT) reported only RR, and not the number of
events, for sex-specific subgroup outcomes, thus it was not
possible enter continuous data (number of events) for this trial
[19]. The significance level for all tests of outcome was set at
p 0.05. The assumption of homogeneity between the
treatment effects in different trials was tested with the Q and
the I square statistic. If the assumption of homogeneity was
rejected (p b 0.10), additional analyses were done with a
random effects model [20]. Participants could contribute
only one event to the calculation for each outcome, but could
contribute one event to each of the separate analyses of
different outcomes.
Studies of poorer methodological quality, such as unblinded or open-labelled trials may exhibit exaggerated
treatment effect and the Jadad et al. [8] scores were utilized to
evaluate the methodological quality of the included trials.

Our original searches identified 1543 titles, after

eliminating ineligible studies by review of titles and
abstracts, we reviewed the full text of 135 articles. Of 12
[916,2427] identified studies that initially seemed to fit all
inclusion criteria, ASPEN [24], CARDS [25] and two other
studies were excluded [26,27] as we did not obtain sexspecific data on outcomes, despite we contacted the principal
investigators. Thus, we found 8 studies to be both eligible
and that contained data stratified by sex for inclusion in the
systematic review [916] (Fig. 1). Study population of
PROSPER [15] was equally divided between persons with or
without prior CHD. Separate estimates for the effects of
lipid-lowering therapy in primary and secondary prevention
in PROSPER were not published or available. Because the
potential importance of this large trial we conducted
sensitivity analysis, whereby we assessed the impact on
outcomes of including and excluding it. Also HPS [13] trial
was not a primary prevention study at all, for this reason we
conducted the same sensitivity analysis such as PROSPER
[15] study. Characteristics of the 8 eligible trials are
described in (Table 1). The total number of women included
in the trials was 19,052 and 30,194 men. Duration of treatment
ranged from 2.3 to 5.3 years and averaged 3.9 years. Eligibility
criteria trials required at least mild or moderate hyperlipidemia
(ACAPS [9], AFCAPS [10], ALLHAT [11], ASCOT [12],
WOSCOPS [16]), or required a range of cholesterol levels that
would include some participants in the normal range
(AFCAPS [10], HPS [13], MEGA [14], PROSPER [15]).
Statins utilized in the trials were atorvastatin (ASCOT [12]),
lovastatin (ACAPS [9], AFCAPS [10]), pravastatin (ALLHAT
[11], MEGA [14], PROSPER [15], WOSCOPS [16]). All
trials were double blinded or Prospective Randomized Open
Blinded Endpoint (PROBE), quality score is expressed as
Jadad et al. [8] score (Table 1). The clinical outcomes
evaluated were total mortality and CHD events, as only these

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M. Petretta et al. / International Journal of Cardiology 138 (2010) 2531

two outcomes were possible to extract from published articles.

Although we contacted the principal investigators of trials to
obtain more detailed data on other clinical outcomes stratified
by sex, none of them shared their unpublished results with our
meta-analysis.
3.1. Total mortality
Four trials [1012,14,16] reported the effect of statins on
total mortality among 20,426 men without prior cardiovascular disease (Fig. 2). One of these trials (MEGA) [14] reported a significant lower risk of total mortality with statins.
The summary relative risk (RR) for primary prevention of
mortality was 0.93 (95% Confidence Interval (CI) 0.83
1.04; comparison p = 0.22; heterogeneity p = 0.408) (Fig. 2).
The results of ALLHAT [11] have been challenged because it
was unblinded, 32% of the usual care participants started
taking lipid-lowering drugs at some point during the study,
and a smaller than expected differential in total cholesterol
was found between the treatment and usual care groups
(9.6%). Thus, we performed sensitivity analysis excluding
ALLHAT [11], the summary RR was not significantly
different (RR 0.84; CI 0.691.00; comparison p = 0.06; heterogeneity p = 0.571).
Four trials [911,14] reported the effect of statins on
total mortality among 12,076 women without prior cardiovascular disease (Fig. 3). No trial showed a significant
lower risk of mortality with statins and the summary RR
was 0.96 (CI 0.811.13; comparison p = 0.61 heterogeneity
p = 0.207) (Fig. 3). Furthermore, also in this case, excluding
ALLHAT [11], the summary RR was not significantly
different (RR 0.84; CI 0.541.30; comparison p = 0.42;
heterogeneity p = 0.13).

3.2. CHD events

Seven trials [1016] reported the effect of statins on
CHD events among 27,382 men. As PROSPER [15] and
HPS [13] were not primary prevention trials at all, we
performed our analysis with and without these studies. All
but one trial (ALLHAT [11]) showed a significant lower risk
of CHD events with statins and including all trials the
summary RR was 0.59 (95% CI 0.480.74; comparison p =
0.0001; heterogeneity p = 0.0001) (Fig. 4), however
excluding ALLHAT [11] the result did not substantially
change (RR 0.55; 95% CI 0.430.71; comparison p = 0.0001;
heterogeneity p = 0.0001). Meta-analysis without PROSPER
[15] resulted in a summary RR of 0.60 (95% CI 0.460.77;
comparison p = 0.0001; heterogeneity p = 0.0001) and
did not significantly change if only HPS [13] was excluded
(RR 0.55; 95% CI 0.440.70; comparison p = 0.0001; heterogeneity p = 0.001). The same occurred if both studies
(HPS [13] and PROSPER [15]) were not included in metaanalysis (RR 0.55; 95% CI 0.410.75; comparison p =
0.0001; heterogeneity p = 0.0001).
As for women, six trials [1015] reported the effect of
statins on CHD events among 17,610 subjects. In this
case, only HPS [13] study showed a significant lower risk of
CHD events with statins and the summary RR, including all
trials, was weakly significant: 0.89 (95% CI 0.791.00;
comparison p = 0.05; heterogeneity p = 0.297) (Fig. 5).
Excluding only PROSPER [15] the result did not significantly change (RR 0.86; 95% CI 0.740.99; comparison
p = 0.04; heterogeneity p = 0.25). However excluding only
HPS [13], significant protection with statins disappeared (RR 0.96 CI 0.831.10; comparison p = 0.54; heterogeneity p = 0.557). Excluding both PROSPER [14] and

Fig. 2. Relative risks of statin therapy on total mortality in men. Solid squares represent odds ratios in trials and have a size proportional to the number of events.
The 95% confidence intervals for individual trials are denoted by lines and those for the pooled odd ratios by empty diamonds. Acronyms of trials are explained
in the text. NR: not reported; NA: not applicable.

M. Petretta et al. / International Journal of Cardiology 138 (2010) 2531

29

Fig. 3. Relative risks of statin therapy on total mortality in women. Solid squares represent odds ratios in trials and have a size proportional to the number of
events. The 95% confidence intervals for individual trials are denoted by lines and those for the pooled odd ratios by empty diamonds. Acronyms of trials are
explained in the text. NR: not reported; NA: not applicable.

HPS [13], protection against CHD events with statin therapy did not reach significance again (RR 0.95 CI 0.78
1.16; comparison p = 0.562; heterogeneity p = 0.39). Excluding only ALLHAT [11] the summary RR yielded statistical
significance for CHD events risk reduction (RR 0.84 CI
0.730.97; comparison p = 0.018; heterogeneity p = 0.38).
However, in this case, this summary RR is strongly influenced by HPS, that, as said above, is not at all of primary
prevention.

3.3. Assessments for heterogeneity and publication bias

There was statistical evidence of heterogeneity in summary estimate of CHD events in men. However, in this case
we performed meta-analysis with a random effects model, in
order to obtain more conservative results [20]. Furthermore,
we made sensitivity analysis including and excluding trials
that could have biased the summary estimates, nevertheless
significant heterogeneity remained.

Fig. 4. Relative risks of statin therapy on CHD in men. Solid squares represent odds ratios in trials and have a size proportional to the number of events. The 95%
confidence intervals for individual trials are denoted by lines and those for the pooled odd ratios by empty diamonds. Acronyms of trials are explained in the text.
NR: not reported; NA: not applicable.

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M. Petretta et al. / International Journal of Cardiology 138 (2010) 2531

Fig. 5. Relative risks of statin therapy on CHD in women. Solid squares represent odds ratios in trials and have a size proportional to the number of events. The
95% confidence intervals for individual trials are denoted by lines and those for the pooled odd ratios by empty diamonds. Acronyms of trials are explained in the
text. NR: not reported; NA: not applicable.

There was no evidence of publication bias in any of the

summary estimates both with the Begg and Egger method.
4. Discussion
Our study showed that statin therapy reduced the risk of
CHD events in men without prior cardiovascular disease.
However in women, the evidence of this protection is less
clear. In men there was a great risk reduction (44%) that
did not substantially change in sensitivity analysis, that is
excluding trials not of primary prevention at all (HPS [13]
and PROSPER [14]). In addiction, even excluding ALLHAT [11] (that was the only trial not reporting a significant
risk reduction) from analysis, a significant reduction of
CHD events remained. Differently, for women treated with
statins in primary prevention, we found a risk reduction of
CHD of borderline significance. However, excluding HPS
trial, the borderline significance disappeared, becoming
clearly not significant. Indeed, as it has been demonstrated
the protective role for CHD events of lipid lowering treatment in secondary prevention [5,28], the great proportion
of patients with prior cardiovascular disease included in
HPS study, has probably influenced the summary RR. About
the sex-specific efficacy of primary prevention of cardiovascular outcomes, the result of our meta-analysis on CHD
events is concordant with the overview of Berger et al. [29].
The reasons of these different effects have not been clarified yet. For this outcome, our results are also in agreement with the meta-analysis of Walsh et al. that did not
show a significant reduction of CHD events in women [5].
However, although we added the results of MEGA trial, that
enrolled a great proportion of women (more than 5000) and

that showed benefit of statin therapy similar to that seen

in men, the reduction in CHD events did not reach the
significance.
For the trials reporting total mortality, statin therapy does
not appear to have a beneficial effect for both men and
women without previous cardiovascular disease over the 2.8to 5.3 year study period in the available trials, although a
longer length of follow-up may be necessary to find a
reduction in mortality. A prior systematic review of trials of
statin therapy in primary prevention of cardiovascular disease, published before the results of the MEGA trial was
available [30], however results were not stratified by sex.
Indeed, as about 70% of the participants included in that
review were men, the results primarily reflect the effects of
statins in men. Recently it has been published a sex-specific
meta-analysis [31] assessing the impact of gender on statin
therapy. Even though they found a risk reduction for cardiovascular outcomes, they did not perform a separate analysis
for primary and secondary prevention trials. Although 11
clinical trials on statin therapy included women (WOSCOPS
study included only men), only 8 published results by sex.
Despite we contacted study investigators, we did not obtain
data on women for the other three studies. As data on total
mortality, CHD mortality, nonfatal MI, CHD events, and
revascularization procedures were not available from each
trial, we contacted study investigators of all trials also to
obtain sex stratified results on these not published outcomes.
However, our request was not satisfied by study investigators,
and that limited our ability to assess the effect of statins on
some outcomes. In addition, because results were generally
not published for differing drug doses, no information regarding dose is available.

M. Petretta et al. / International Journal of Cardiology 138 (2010) 2531

Our findings suggest that among persons without cardiovascular disease, statins may not be as effective in women
as in men without cardiovascular disease. However, as the
number of events in the 8 available primary prevention trials
was small, our power to observe a modest reduction in CHD
risk could be limited, yielding imprecise effect estimates. In
addition, the average length of the follow-up of the primary
prevention trials was only 3.9 years, and it is possible that
a longer duration of treatment may have resulted in a larger
reduction in CHD outcomes. Furthermore, as we were not
able to obtain data from 4 trials, and in particular from
ASPEN and CARDS study investigators, could have potentially biased the results. Clinicians could benefit from
combining sex-specific data from all of the completed trials in
an individual patient-level meta-analysis.
Acknowledgement
The authors of this manuscript have certified that they
comply with the Principles of Ethical Publishing in the
International Journal of Cardiology [32].
References
[1] Bello N, Mosca L. Epidemiology of coronary heart disease in women.
Prog Cardiovasc Dis 2004;46:28795.
[2] Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for
cardiovascular disease prevention in women: 2007 update. Circulation
2007;115:1481501.
[3] Kim C, Hofer TP, Kerr EA. Review of evidence and explanations
for suboptimal screening and treatment of dyslipidemia in women. A
conceptual model. J Gen Intern Med 2003;18:85463.
[4] Persell SD, Maviglia SM, Bates DW, Ayanian JZ. Ambulatory
hypercholesterolemia management in patients with atherosclerosis.
Gender and race differences in processes and outcomes. J Gen Intern
Med 2005;20:12330.
[5] Walsh JME, Pignone M. Drug treatment of hyperlipidemia in women.
JAMA 2004;291:224352.
[6] Mizuno K, Nakaya N, Ohashi Y, et al. Usefulness of pravastatin in
primary prevention of cardiovascular events in women: analysis of the
Management of Elevated Cholesterol in the Primary Prevention Group
of Adult Japanese (MEGA study). Circulation 2008;4:494502.
[7] Moher D, et al, for the QUOROM Group. Improving the quality
of reports of meta-analyses of randomised controlled trials: the
QUOROM statement. Lancet 1999;354:1896900.
[8] Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports
of randomized clinical trials: is blinding necessary? Control Clin Trials
1996;17:112.
[9] Furberg CD, Adams Jr HP, Applegate, et al. Effect of lovastatin on
early carotid atherosclerosis and cardiovascular events. Asymptomatic
Carotid Artery Progression Study (ACAPS) Research Group. Circulation 1994;90:167987.
[10] Downs JR, Clearfield M, Tyroler HA, et al. Primary prevention of
acute coronary events with lovastatin in men and women with average
cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas
Coronary Atherosclerosis Prevention Study. JAMA 1998 May 27;279:
161522.
[11] ALLHAT Officers and Coordinators for the ALLHAT Collaborative
Research Group. The Antihypertensive and Lipid-Lowering Treatment
to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs
usual care. JAMA 2002;288:2998.

31

[12] Sever PS, et al, for the ASCOT investigators. Prevention of coronary
and stroke events with atorvastatin in hypertensive patients who have
average or lower-than-average cholesterol concentrations, in the AngloScandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOTLLA): a multicentre randomised controlled trial. Lancet 2003;361:
114958.
[13] 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;360:722.
[14] Nakamura H, et al, for the MEGA Study Group. Primary prevention
of cardiovascular disease with pravastatin in Japan (MEGA Study):
a prospective randomised controlled trial. Lancet 2006;368:115563.
[15] Shepherd J, Blauw GJ, Murphy MB, et al. 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;360:162330.
[16] Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart
disease with pravastatin in men with hypercholesterolemia. West of
Scotland Coronary Prevention Study (WOSCOPS) Group. N Engl J
Med 1995;333:1301.
[17] Sharp S, Sterne J. Meta-analysis. Stata Technical Bulletin Reprints
1998;7(STB-38):1008.
[18] Haldane J. The estimation and significance of the logarithm of a ratio
of frequencies. Ann Hum Genet 1955;20:30914.
[19] Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for
meta-analysis in medical research. Chichester: Wiley; 2000. p. 58.
[20] Woodward M. Epidemiology, study design and data analysis. London:
Chapman and Hall; 1999.
[21] Mantel N, Haenszel W. Statistical aspects of the analysis of data from
retrospective studies of disease. J Natl Cancer Inst 1959;22:71948.
[22] Begg CB, Mazumdar M. Operating characteristics of a rank correlation
test for publication bias. Biometrics 1994;50:1088101.
[23] Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315:62934.
[24] Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of
atorvastatin in the prevention of cardiovascular end points in subjects
with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary
Heart Disease Endpoints in non-insulin-dependent diabetes mellitus
(ASPEN). Diabetes Care 2006;29:147885.
[25] Raikou M, McGuire A, Colhoun HM, et al. Primary prevention of
cardiovascular disease with atorvastatin in type 2 diabetes in the
Collaborative Atorvastatin Diabetes Study (CARDS): multicentre
randomised placebo-controlled trial. Lancet 2004;364:68596.
[26] Herd JA, Ballantyne CM, Farmer JA, et al. Effects of fluvastatin on
coronary atherosclerosis in patients with mild to moderate cholesterol
elevations (Lipoprotein and Coronary Atherosclerosis Study [LCAS]).
Am J Cardiol 1997;80:27886.
[27] 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;72:10317.
[28] Stramba-Badiale M, Fox KM, Priori SG, et al. Cardiovascular diseases
in women: a statement from the policy conference of the European
Society of Cardiology. Eur Heart J 2006;27:9941005.
[29] Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G,
Brown DL. Aspirin for the primary prevention of cardiovascular events
in women and men: a sex-specific meta-analysis of randomized
controlled trials. JAMA 2006;295:30613.
[30] Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary
prevention of cardiovascular diseases with statin therapy: a meta-analysis
of randomized controlled trials. Arch Intern Med 2006;166: 230713.
[31] Dale KM, Coleman CI, Shah SA, Patel AA, Kluger J, White CM.
Impact of gender on statin efficacy. Curr Med Res Opin 2007;23:
56574.
[32] Coats AJ. Ethical authorship and publishing. Int J Cardiol
2009;131:14950.