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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].

Meta-analysis of statin effects in women versus men

WJ Kostis, JQ Cheng, JM Dobrzynski, J Cabrera, and JB Kostis.

Review published: 2012.

Link to full article: [Journal publisher]

CRD summary

The authors concluded that statins decreased cardiovascular events and all-cause mortality in both women and men and this was present in primary and secondary prevention trials. The authors’ conclusions reflect the evidence presented. Potential issues with the review process and power of the analysis which suggest that the authors’ cautions regarding interpretation of the findings should be heeded.

Authors' objectives

To assess the effects of statin therapy on cardiovascular events in women compared to men.

Searching

MEDLINE, The Cochrane Library, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and ClinicalTrials.gov were searched up to June 2010. The search strategy was reported.

Study selection

Double-blind randomised controlled trials (RCTs) that assessed effects of statin therapy on gender-specific all-cause mortality were eligible for inclusion if they included at least 100 patients and reported at least five deaths per randomised group. The primary endpoints stated by the included trials were also of interest.

Most participants in the included trials were men (31% to 86%). Ages ranged from 58 to 75 years. Zero to 35.2% of patients had diabetes and between 22% and 100% had hypertension. Zero to 100% of patients had prior cardiovascular disease and 5% to 63% were current smokers. Some trials were primary prevention and some were secondary prevention. Intervention treatments were lovastatin, pravastatin, atorvastatin, rosuvastatin and simvastatin. Doses ranged from 8.3mg and 320.0mg. Controls received placebo, usual care (not specified) or a smaller dose of a statin. Aspirin was administered to 57.6% patients. Primary endpoints of the included studies were reported in the review.

The authors reported that the review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement. Two reviewers screened studies for inclusion.

Assessment of study quality

Trial methodology was assessed for similarity of baseline characteristics, defined eligibility criteria, blinding, use of placebo or other control, intention-to-treat analysis, adherence and loss to follow-up.

The authors did not state how many reviewers performed the assessment.

Data extraction

Rates of occurrence for primary endpoints and all-cause mortality were extracted to calculate absolute risks and relative risks, ultimately to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the population as a whole and by gender. Primary authors were contacted for missing data.

The authors did not state how many reviewers extracted data.

Methods of synthesis

A random-effects model was used to calculate weighted pooled odds ratios and 95% CIs for the whole population and by gender. Statistical heterogeneity was assessed using the Q statistic.

Additional analyses were performed by type of prevention (primary, secondary and mixed), level of baseline risk (high annual risk of mortality versus medium risk versus low risk) and by type of endpoint (stroke, coronary heart disease). Sensitivity analysis was performed by removing one trial at a time to examine the effects of each trial on the results. Multivariate meta-regression was performed to assess whether trial characteristics influenced the differences between women and men.

Publication bias was examined using Duval and Tweedie’s trim and fill method and the fail-safe N models of Rosenthal and Orwin.

Results of the review

Eighteen randomised controlled trials (141,235 participants; 40,275 women) were included in the review. There were 13,710 deaths (3,898 deaths in studies with sex-specific mortality data). All trials were randomised, reported allocation concealment, defined eligibility, had similar baseline characteristics, used intention-to-treat analyses and reported adherence details (between 63% and 98.8%). Three trials were not double blind. Seventeen trials were funded by the pharmaceutical industry. Follow-up ranged from 22.8 to 80.4 months.

On average, 85.5% (standard deviation 9.9%) of patients who were allocated to active treatment received it compared to 17.2% (standard deviation 9.9%) of patients in control groups.

Primary endpoints: Statin therapy statistically significantly reduced primary endpoints in women (OR 0.81, 95% CI 0.75 to 0.89) and men (OR 0.77, 95% CI 0.71 to 0.83). There was a non-significant trend towards greater benefit in men.

Sensitivity analysis did not significantly alter the findings. Analyses by type of prevention, level of baseline risk and type of endpoint did not significantly alter the findings. Meta-regression indicated factors that may influence the observed differences between women and men: percentage of men, percentage with cardiovascular disease, percentage of smokers, percentage taking aspirin and mean age.

All-cause mortality: Statin therapy reduced all-cause mortality in women (OR 0.90, 95% CI 0.82 to 0.99) and men (OR 0.84, 95% CI 0.77 to 0.92). Findings were similar in women when primary prevention trials were analysed separately but not for secondary prevention trials. The opposite was true for men.

The authors suggested there may be potential for publication bias.

Cost information

One trial indicated that the estimated cost of preventing one cardiovascular event with rosuvastatin was $287,000 and the price of generic statins would be lower.

Authors' conclusions

Statins decreased cardiovascular events and all-cause mortality in both women and men in both primary and secondary prevention trials.

CRD commentary

The review question and supporting inclusion criteria were broadly defined. Appropriate databases were searched to identify relevant articles. Grey literature were not sought so potentially relevant data may have been missed. Restricting eligible trials by the number of deaths will have reduced the evidence base. The authors acknowledged potential for publication bias. Appropriate criteria were used to assess trial methodology. It was unclear why three trials that were not double blind were included when the authors specified double blinding for eligible trials. Only study selection was reported to have been performed in duplicate so reviewer error and bias could not be ruled out. Statistical heterogeneity was assessed but the findings were not reported. There were considerable differences between trials (for example, between patients and defined primary outcomes) which suggested potential for clinical and methodological heterogeneity. Attempts were made to investigate potential factors that influenced the results. The authors suggested that the exclusion of studies without sex-specific data may have reduced the power of the analyses. It was unclear how the difference in adherence rates and uneven male/female proportions may have impacted on the findings.

The authors’ conclusions reflect the evidence presented. Potential issues with the review process and power of the analysis (particularly in terms of separate analysis for males and females) suggest that the authors’ cautions regarding interpretation of the findings should be heeded.

Implications of the review for practice and research

Practice: The authors stated that statin therapy should be used in appropriate patients without regard to gender. However, the evidence presented should not be over-interpreted.

Research: The authors stated that analysis of individual patient data may provide more precise estimates of effect than those reported in the current review.

Funding

Robert Wood Johnson Foundation, USA.

Bibliographic details

Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. Journal of the American College of Cardiology 2012; 59(6): 572-582. [PubMed: 22300691]

Indexing Status

Subject indexing assigned by NLM

MeSH

Cardiovascular Diseases /epidemiology /prevention & control; Cause of Death /trends; Confidence Intervals; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors /pharmacology; Male; Morbidity /trends; Odds Ratio; Sex Distribution; Sex Factors; World Health

AccessionNumber

12012009764

Database entry date

23/10/2012

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: 22300691

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