Journal of the American College of Cardiology Vol. 59, No. 6, 2012© 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. doi:10.1016/j.jacc.2011.11.008

EDITORIAL COMMENT

Controversy andConsensus About Statin UseIt Is Not About the Sex*

Lori Mosca, MD, MPH, PHD

New York, New York

If statistics is a science of probability then Sir William Oslerexpressed the limitations of its applications when he artic-ulated “Medicine is a science of uncertainty and an art ofprobability” (1). Despite widespread consensus about statinuse for the secondary prevention of cardiovascular disease(CVD) in both sexes, there has been substantial debate withregard to the use of statins for primary prevention amongwomen. Much of the discourse has centered on the fact thatwomen have not participated in primary prevention trials tothat extent that men have; therefore, less-definitive conclu-sions can be drawn about the likelihood of benefits and risksamong women. The short-term absolute risk of a futurecardiovascular event among women is substantially lowerthan men in a primary prevention population, furtheramplifying the challenge of under-representation of womenin primary prevention trials. The potential for poolingindividual studies to provide a more precise single estimateof a treatment effect was recognized over 100 years ago bythe statistician Karl Pearson as a method to reduce error indrawing conclusions based on small group sizes (2).

See page 572

The current meta-analysis by Kostis et al. (3) in this issueof the Journal, which included trials with 141,235 partici-pants, adds unique information to the existing body ofevidence aimed to examine a possible interaction betweensex and the effects of statins on the prevention of CVD. Theauthors conducted a systematic published data search toidentify relevant randomized controlled clinical trials re-porting sex-specific outcome data. Of the more than 2,300potential studies identified, 18 met all the inclusion criteria

*Editorials published in the Journal of the American College of Cardiology reflect theviews of the authors and do not necessarily represent the views of JACC or theAmerican College of Cardiology. Dr. Mosca is supported by a National Institutes ofHealth Research Career Award K24HL076346; has received consulting fees andhonoraria from Gilead Sciences, Inc. and Sanofi-Aventis; is an advisor and consultantfor Rowpar; and is a member of the Institute of Medicine Committee on Women’sHealth Research.

From the NewYork-Presbyterian Hospital/Columbia University Medical Center,New York, New York.

for the meta-analysis (8 primary prevention trials), 2 in-cluded sex-specific data on adverse effects, and all but 1 werefunded by the pharmaceutical industry. Pooled weightedtreatment effects were calculated overall and by sex withrandom effects models, and then pre-specified analyses wereconducted according to the category of prevention trial(primary, secondary, or mixed), the classification of end-point (coronary or stroke), the type of control (low-dosestatin or usual care/placebo), and the annual mortality riskof the study population (high, medium, or low).

The authors concluded that the benefit of statins weresignificant for both sexes for primary and secondary preven-tion; the benefits of treatment were observed, regardless ofthe type of endpoint studied, the type of control used, or themortality risk of the population. Additionally, the mortalitybenefit with statins did not differ significantly by sex(approximately 4,000 deaths had sex-specific mortalitydata), and all-cause mortality statin benefits were significantin women when primary prevention trials were analyzedseparately. The reduction in CVD event rates with treat-ment versus control was not different in women comparedwith men (19% and 23%, respectively). The CVD benefitfor secondary prevention was greater than for primaryprevention but both were significant among women (oddsratio: 0.78 vs. 0.85, respectively). The benefits of statinswere robust across different populations of risk and unex-pectedly showed greater benefit in studies with lowermortality risk populations, a possible artifact of internationaltrial variations and differences in study design.

The finding of no interaction by sex in this contemporarymeta-analysis is concordant with prior meta-analyses thatwere limited by smaller numbers of women and suggestsstatin therapy has similar proportional benefits for men andwomen, regardless of the type of endpoint studied or thelevel of population risk (4,5). Although pooling studiesmight solve problems related to small sample sizes withlimited power, it is important to recognize that by increas-ing the numbers of women in meta-analyses the precision ofa point estimate might increase but the accuracy or validityof the treatment effect might not necessarily be improved.Meta-analyses have well-recognized limitations, and thebiases of individual studies might be magnified rather thanmitigated when pooled together. Remember the mantra“garbage in, garbage out”? In the case of Kostis et al. (3), theauthors did due diligence by using selective inclusion criteriato analyze the highest quality evidence with highly sophis-ticated statistical techniques; they conducted sensitivityanalysis, systematically examined publication bias, andtested for interaction by several important parameters.

Ironically, the problem the study faced remained one ofsmall numbers. There were only a handful of primaryprevention studies, and only 4 were classified as low-riskpopulations that could inform the controversy around statinuse in women. One of the largest contributors to the

analysis was the MEGA (Primary prevention of cardiovas-

584 Mosca JACC Vol. 59, No. 6, 2012Sex Differences and Statin Use February 7, 2012:583–4

cular disease with pravastatin in Japan) trial, which investi-gated the effects of open label pravastatin in a Japanesepopulation with hypercholesterolemia (6). Older womenhad a more pronounced benefit than younger women—although effects were similar to men—suggesting that evenwithin a primary prevention population a benefit gradient isobserved (7). The meta-analysis also included the JUPITERtrial (Justification for the Use of Statins in Prevention: AnIntervention Trial Evaluating Rosuvastatin), which individ-ually documented a similar relative risk reduction for menand women with elevated levels of inflammation withoutclinical CVD who were randomized to rosuvastatin com-pared with placebo (8). Some have interpreted the data asnot supporting the use of statins for the primary preventionin women—despite the JUPITER trial enrolling nearly7,000 women—because the trial was “flawed,” had a shortfollow-up, and might not readily generalize to other primaryprevention populations (9). Concerns have also been raisedabout the potential long-term safety of statins for primaryprevention in both men and women, due to a potentialincreased risk of incident diabetes that might not be fullyrealized in short-term trials (10).

Can one conclude that this well-conducted meta-analysiscame to the right conclusion? Beyond the inherent limita-tions of meta-analytic approaches and intrinsic biases withinthe individual studies, there are other issues to consider indrawing conclusions about statin use on the basis of thedata. The focus of the analyses was relative risk reduction,and there was limited assessment of risk or costs of therapy.The authors came to the statistical conclusion that sex doesnot matter when it comes to the benefits of statins, all otherthings being considered equal. Agreed, but if sex doesn’tmatter, what does? A recent Cochrane review of theevidence for statins in primary prevention suggests that theannual mortality risk of the patient should drive the decisionabout use of statins in primary prevention (11). Womenwithout CVD have a lower annual mortality risk and lowerCVD risk than men without CVD. Therefore, the absolutebenefit of statins will typically be less for women than men,suggesting it might be appropriate that women receivestatins less frequently than men in the setting of primaryprevention. The current meta-analysis provides informationabout sex-specific relative risk benefit and not absolutebenefit. Both the absolute risk of CVD and the proportion-ate risk reduction associated with statin therapy are neededto make informed clinical choices with regard to the use ofstatins for primary prevention. Although the latter might besimilar for the sexes, the former might be quite different.

Did the authors come to the correct clinical conclusionabout the data? Perhaps, but no data about individualbaseline risk level were evaluated for potential sex differencesin statin effectiveness; within each primary prevention pop-ulation there might be substantial heterogeneity of risk.Moreover, the authors did not have enough data to critically

evaluate adverse side effects, because only 2 studies provided

sex-specific data. Adverse outcomes are important to studyin pooled analyses, because despite their low frequency, theyare clinically important. But scientists cannot do pooledanalyses of adverse effects according to sex if individualstudies do not provide the data.

The Institute of Medicine has called for more uniformreporting of sex-specific data with respect to both efficacyand safety (12). Sex-specific results in cardiovascular pre-vention trials should be provided for relative and absolutebenefits, adverse outcomes, and cost-effectiveness. Onlythen we will know with less uncertainty whether what isgood for the gander is also good for the goose. Medicine isstill an art.

Reprint requests and correspondence: Dr. Lori Mosca, Colum-bia University Medical Center, 601 West 168th Street, Suite 43,New York, New York 10032. E-mail: ljm10@columbia.edu.

REFERENCES

1. Sir William Osler. Aphorisms from his bedside teachings and writings,collected by Robert Bennett Bean, edited by William Bennett Bean.New York, NY: Henry Schuman Inc., 1950.

2. Pearson K. Report on certain enteric fever inoculation statistics. BrMed J 1904;3:1243–6.

3. Kostis WJ, Cheng JQ, Dobrzynski JM, Cabrera J, Kostis JB. Meta-analysis of statin effects in women versus men. J Am Coll Cardiol2012;59:572–82.

4. Brugts JJ, Hoeks SE, Gotto AM, et al. The benefits of statins inpeople without established cardiovascular disease but with cardiovas-cular risk factors: meta-analysis of randomised controlled trials. BMJ2009;338:b2376.

5. Baigent C, Keech A, Kearney PM, et al., for the CholesterolTreatment Trialists’ (CTT) Collaborators. Efficacy and safety ofcholesterol-lowering treatment: prospective meta-analysis of data from90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78.

6. Nakamuro H, Arakawa K, Itakura H, et al. Primary prevention ofcardiovascular disease with pravastatin in Japan (MEGA study): aprospective randomized controlled trial. Lancet 2006;368:1155–63.

7. Mizuno K, Nakaya N, Ohashi Y, et al., for the MEGA Study Group.Usefulness of pravastatin in primary prevention of cardiovascularevents in women. Analysis of the management of elevated cholesterolin primary prevention group of adult Japanese (MEGA Study).Circulation 2008:I17:494–502.

8. Mora S, Glynn RJ, Hsia J, et al. Statins for the primary prevention ofcardiovascular events in women with elevated high-sensitivityC-reactive protein or dyslipidemia. Results from the Justification forthe Use of Statins in Prevention: an Intervention Trial EvaluatingRosuvastatin (JUPITER) and meta-analysis of women from primaryprevention trials. Circulation 2010;121:1069–77.

9. De Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering,cardiovascular diseases, and the rosuvastatin-JUPITER controversy.Arch Intern Med 2010;170:1032–36.

10. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incidentdiabetes: a collaborative meta-analysis of randomized statin trials.Lancet 2010;375:735–42.

11. Taylor F, Ward K, Moore TH, et al. Statins for the primaryprevention of cardiovascular disease. Cochrane Database of Syst Rev2011:CD004816.

12. Adler NE, Adashi EY, Aguilar-Gaxiola S, et al., for the Institute ofMedicine’s (IOM) Committee on Women’s Health Research. Women’sHealth Research: Progress, Pitfalls, and Promise. Washington, DC: TheNational Academies Press.

Key Words: cardiovascular disease y LDL y lipids y statins y women.