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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials

JJ Brugts, T Yetgin, SE Hoeks, AM Gotto, J Shepherd, RG Westendorp, AJ de Craen, RH Knopp, H Nakamura, P Ridker, R van Domburg, and JW Deckers.

Review published: 2009.

CRD summary

This generally well-conducted review concluded that statin use in patients without established cardiovascular disease, but with cardiovascular risk factors, was associated with significantly improved survival and large reductions in the risk of major cardiovascular events. This conclusion reflected the results of an appropriate synthesis of large, high-quality trials and is likely to be reliable.

Authors' objectives

To determine the effectiveness of statins in reducing mortality and major coronary and cerebrovascular events in individuals without established cardiovascular disease, but with cardiovascular risk factors.


Cochrane Central Register of Controlled Trials, MEDLINE (from 1990), EMBASE (from 1980), DARE and ACP Journal Club were searched up to November 2008. Search terms were reported. References were checked and the MEDLINE related articles function was used.

Study selection

Randomised controlled trials (RCTs) that compared statins with placebo, an active control or usual care in a population where at least 80 per cent did not have established cardiovascular disease, or where data from this group were reported separately, were eligible for inclusion. Trials were required to report mortality or cardiovascular events as primary outcomes and to have follow-up for at least one year. Studies in specific clinical populations such as renal patients were excluded from the review.

Included studies used pravastatin, lovastatin, atorvastatin, simvastatin or rosuvastatin. Doses ranged from 10 mg/day to 40 mg/day. All included studies except one were placebo controlled. Where reported, the mean age of patients ranged from 55 to 75 years (overall mean 63 years, range 40 to 80). The proportion of women ranged from 0 to 68 per cent (34 per cent overall). Some trials enrolled only patients with diabetes. In other studies the proportion of patients with diabetes ranged from 0 to 34 per cent (23 per cent overall).

The authors stated neither how the papers were selected for the review nor how many reviewers performed the selection.

Assessment of study quality

The studies were assessed for validity by two independent reviewers using criteria of allocation concealment, use of intention-to-treat (ITT) analysis and completeness of follow up. The studies were also scored using the Jadad scale, which awards up to 5 points for the criteria of randomisation, blinding and treatment of withdrawals and dropouts; a score of at least 4 points was regarded as indicating sufficient quality. Disagreements were resolved through consensus.

Data extraction

Data were extracted on numbers of patients in each group who died or experienced major coronary or cerebrovascular events during follow-up. Odds ratios (OR) with 95% confidence intervals (CI) were calculated for each outcome. Study authors were contacted for additional subgroup data. Two independent reviewers extracted the data using a standardised form. Disagreements were resolved through consensus.

Methods of synthesis

Trials were combined using both fixed- and random-effects models to calculate pooled ORs with 95% CIs, with the random-effects model the primary analysis. Sensitivity analyses were conducted to explore the effects of excluding trials that included data on a small number of secondary prevention patients and the effects of using original results without extended follow up from another trial. Subgroup analyses were used to assess efficacy in predefined subgroups of patients (those aged under 65 years versus over 65 years; male versus female; and with diabetes versus without diabetes) where at least two studies reported such data. Statistical heterogeneity between studies was assessed using the X2 and I2 tests. Publication bias was assessed by examination of funnel plots and by the Egger test.

Results of the review

Ten RCTs (N = 70,388) were included in the review. Sample sizes ranged from 1,905 to 17,802. Nine trials were double-blinded. All scored at least four points on the Jadad scale. Mean follow-up was 4.1 years (range 1.9 to 5.3 years).

Mortality at mean follow-up was statistically significantly lower in the statin groups than in the control groups (5.1% versus 5.7%; OR 0.88, 95% CI: 0.81, 0.96, nine RCTs). A similar effect was found for the occurrence of a major coronary event (4.1% versus 5.4%, OR 0.70, 95% CI: 0.61, 0.81, eight RCTs) and a major cerebrovascular event (1.9% versus 2.3%, OR 0.81, 95% CI: 0.71, 0.93, nine RCTs). There was no statistically significant difference in the incidence of cancer between treatment arms.

Statistical heterogeneity was low for all the analyses (I2 = 0% to 27%) except for major coronary events, where heterogeneity was moderate (I2 = 60%). Results were also reported for constituent outcomes of coronary heart disease mortality, non-fatal myocardial infarction and revascularisations. Sensitivity analyses did not materially affect the results of the analyses. The results of subgroup analyses were reported and showed no evidence of a differential effect of statins in any of the predefined subgroups.

There was no evidence of publication bias for any of the primary outcomes.

Authors' conclusions

In patients without established cardiovascular disease, but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.

CRD commentary

The review question was clear and supported by specific inclusion criteria. The authors searched several relevant databases and this reduced their chances of omitting relevant studies. No systematic attempts to locate unpublished studies were reported, but publication bias was assessed and no evidence of it was found. The authors did not report whether language restrictions were used. The authors reported using methods designed to reduce reviewer bias and error in the assessment of validity and the extraction of data, but not in study selection. Appropriate criteria were used for the validity assessment. The use of meta-analyses (including a priori defined subgroup analyses) appeared appropriate. The included studies were large and were assessed as having sufficient validity. There was only limited evidence of statistical heterogeneity. The conclusions of this generally well-conducted review reflected the results of appropriate analysis of good quality evidence and are likely to be reliable.

Implications of the review for practice and research

Practice: The authors stated that it would be wrong to deny the benefits of statin use to people at increased risk for cardiovascular disease. Individuals regarded as being at increased risk were men aged over 65 years with risk factors and older women with diabetes and risk factors.

Research: The authors stated that auxiliary diagnostic or prognostic assessments to improve risk prediction for cardiovascular disease would be useful.



Bibliographic details

Brugts J J, Yetgin T, Hoeks S E, Gotto A M, Shepherd J, Westendorp R G, de Craen A J, Knopp R H, Nakamura H, Ridker P, van Domburg R, Deckers J W. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009; 338: b2376. [PMC free article: PMC2714690] [PubMed: 19567909]

Indexing Status

Subject indexing assigned by NLM


Age Distribution; Aged; Cardiovascular Diseases /prevention & control; Cause of Death; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors /therapeutic use; Male; Middle Aged; Odds Ratio; Randomized Controlled Trials as Topic; Risk Factors; Sex Distribution; Treatment Outcome



Database entry date


Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 19567909


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