This editorial refers to ‘Effect of statins on ventricular tachyarrhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of published and unpublished evi-dence from randomized trials’, by K. Rahimi et al., doi:10.1093/eurheartj/ehs005 Statins are undoubtedly the mainstay in the treatment of hyperlip-idaemia. They are used in primary and secondary prevention of cardiovascular disease.1,2 It is therefore not surprising that statins rank very high among the most successful drugs in the history of medicine. For example, atorvastatin has raked in around US$130 billion for Pfizer during its 14 years on the market, making it cur-rently the world’s bestselling drug.3 Recent studies show that statins possess powerful pleiotropic effects that are independent of their effects on lipids and lipoproteins.4 The pleiotropic effects of statins are credite

Briel, Matthias

Nordmann, Alain J.

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EDITORIALStatins: pleiotropic, but less thanpreviously thoughtAlain J. Nordmann* and Matthias BrielBasel Institute of Clinical Epidemiology and Biostatistics, University Hospital Basel, Hebelstrasse 10, CH-4031 Basel, SwitzerlandOnline publish-ahead-of-print 4 June 2012This editorial refers to ‘Effect of statins on ventriculartachyarrhythmia, cardiac arrest, and sudden cardiac death:a meta-analysis of published and unpublished evidencefrom randomized trials’†, by K. Rahimi et al., on page 1571Statins are undoubtedly the mainstay in the treatment of hyperlip-idaemia. They are used in primary and secondary prevention ofcardiovascular disease.1,2 It is therefore not surprising that statinsrank very high among the most successful drugs in the history ofmedicine. For example, atorvastatin has raked in around US$130billion for Pfizer during its 14 years on the market, making it cur-rently the world’s bestselling drug.3Recent studies show that statins possess powerful pleiotropiceffects that are independent of their effects on lipids andlipoproteins.4 The pleiotropic effects of statins are creditedto several processes that result from the inhibition ofhydroxy-methyl-glutaryl-CoA (HMGCoA) reductase. The maineffect of the drugs is the inhibition of cholesterol and isoprenoid syn-thesis, which results ultimately in the up-regulation of endothelialnitric oxide synthase, an enzyme involved in vascular endothelialfunction. The inhibition of isoprenoid formation also leads to antioxi-dant effects. Additionally, inflammatory markers such as C-reactiveprotein and nuclear factor-kB have been shown to be reduced bystatins, leading to the hypothesis that statins possess anti-inflammatory properties.Other proposedmechanisms for the pleio-tropic effects of statins include immunomodulation, normalization ofsympathetic outflow, plaque stabilization, decreased activationof theblood coagulation cascade, and inhibition of platelet aggregation.4Pathophysiologically, mechanisms such as statin-induced plaquestabilization, changes to the transmembrane ion channel conduc-tion, antioxidant and antiproliferative effects, and a decrease inthe parasympathetic tone may potentially account for an antiar-rhythmic effect of statin therapy which would at least be partiallyindependent of the proven antiatherogenic effects of statintherapy.5 In fact, the use of statins has been suggested to protectagainst various arrythmic disorders,6,7 and a meta-analysis pub-lished in 2008 reported a significant reduction in the incidenceor recurrence of atrial fibrillation in patients in sinus rhythmusing statins.8 However, in a more comprehensive collaborativemeta-analysis of published and unpublished evidence from rando-mized controlled trials, the suggested beneficial effect of statinson atrial fibrillation was clearly not supported.9What about the effect of statin treatment on ventricular arrhythmiccomplications? A very recent meta-analysis suggested that statinsreduce the risk of ventricular tachyarrhythmia in patients with coron-ary artery disease or non-ischaemic cardiomyopathy by aboutone-third.10 Rahimi et al. have now contradicted this finding.11 Intheir meta-analysis of 29 trials with 113 568 participants comparingstatin vs. a control, statin therapy did not significantly reduce therisk of ventricular tachyarrhythmia or cardiac arrest. Although theuse of statins was associated with a significant 10% reduction ofsudden cardiac death, a beneficial direct antiarrhythmic effect inde-pendent of the antiatherogenic effect of statin therapy seems very un-likely. Recently, a large autopsy series reported that coronary arterydisease was responsible for sudden cardiac death in 37% of deathsin the group of those aged 21–30, and in up to 80% of deaths inthe group of those aged 31–40.12 When taking into account thatstatin therapy reduced other (non-sudden) cardiac deaths in includedtrials by 20%, an antiarrhythmic beneficial effect of statins indepen-dendent of their antiatherogenic properties seems unlikely to accountfor the observed reduction in sudden cardiac death.How can the discrepant findings of statin therapy on the occur-rence of ventricular arrhythmias between these two recentmeta-analyses be explained? A closer look at the two meta-analysesmay help in resolving the apparent conflicting evidence. Bothmeta-analyses do not report substantial evidence of heterogeneityand both report a low likelihood of publication bias. However, theabsence of heterogeneity and the low likelihood of publication biasexclude only two of many more potential pitfalls of meta-analysesleading to spurious conclusions. Of the nine identified prospectivestudies with a total of 150 953 individuals in the meta-analysis byWanahita et al.,10 only two were randomized controlled trialswhich together included ,1000 individuals. All the other studieswere observational, with one of these studies contributing 99%*Corresponding author. Tel: +41 61 265 31 00, Fax: +41 61 265 31 09, Email: nordmanna@uhbs.ch or Alain.Nordmann@unibas.ch† doi:10.1093/eurheartj/ehs005.The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.comEuropean Heart Journal (2012) 33, 1551–1552doi:10.1093/eurheartj/ehs027of all individuals included in the analysis. By using a more comprehen-sive literature search and by undertaking the effort to contact authorsof large statin trials to contribute collected, but previously unpub-lished data on the incidence of ventricular arrhythmias, Rahimiet al.11 identified 29 randomized controlled trials comparing statinwith control with 113 568 individuals, .100 times more individualsthan in the two randomized controlled trials identified by Wanahitaet al.10 In addition,Wanahita et al. did not conduct a formal critical ap-praisal of the quality of included studies and failed to report an assess-ment of the risk of bias in included studies as recommended by thePRISMA statement.13 For these reasons, the results of themeta-analysis byWanahita et al.10 can only be regarded as hypothesisgenerating. Rahimi et al.,11 by restricting their meta-analysis to rando-mized controlled trials and collecting all available published and un-published data about the effects of statins on the risk of ventriculararrhythmias, now demonstrate that an antiarrhytmic effect ofstatins is highly unlikely.Nowadays, clinicians quite often are faced with seemingly con-flicting evidence from the medical literature. This may lead to un-certainty in clinical decision-making, especially for busy clinicianswith time constraints not allowing them to read and analysemedical articles more in depth and focusing on abstracts only. Inorder to avoid misleading conclusions from abstracts ofmeta-analyses, all medical journals should adhere to the reportingguidelines as formulated in the PRISMA statement13 that requires astructured abstract with an appraisal of the included studies as wellas a description of the limitations of the meta-analysis.The meta-analysis by Rahimi et al.11 represents the currentlybest available evidence on the effect of statin therapy on ventricu-lar arrhythmias and demonstrates clearly that statin therapy ishighly unlikely to have a beneficial effect for the prevention of ven-tricular arrhythmias. Statins may still possess many pleiotropiceffects, but independent antiarrhythmic effects do not seem tofigure amongst them.Conflict of interest: none declared.References1. Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary preven-tion of coronary heart disease: meta-analysis of randomised trials. BMJ 2000;321:983–986.2. Fletcher GF, Bufalino V, Costa F, Goldstein LB, Jones D, Smaha L, Smith SC Jr,Stone N. Efficacy of drug therapy in the secondary prevention of cardiovasculardisease and stroke. Am J Cardiol 2007;99:1E–35E.3. Lessons from Lipitor and the broken blockbuster drug model. Lancet 2011;378:1976.4. Mihos CG, Salas MJ, Santana O. The pleiotropic effects of thehydroxy-methyl-glutaryl-CoA reductase inhibitors in cardiovascular disease: acomprehensive review. Cardiol Rev 2010;18:298–304.5. Kostapanos MS, Liberopoulos EN, Goudevenos JA, Mikhailidis DP, Elisaf MS. Dostatins have an antiarrhythmic activity? Cardiovasc Res 2007;75:10–20.6. De Sutter J, Tavernier R, De Buyzere M, Jordaens L, De Backer G. Lipid loweringdrugs and recurrences of life-threatening ventricular arrhythmias in high-riskpatients. J Am Coll Cardiol 2000;36:766–772.7. Patti G, Chello M, Candura D, Pasceri V, D’Ambrosio A, Covino E, Di Sciascio G.Randomized trial of atorvastatin for reduction of postoperative atrial fibrillation inpatients undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin forReduction of MYocardial Dysrhythmia After cardiac surgery) study. Circulation2006;114:1455–1461.8. Fauchier L, Pierre B, de Labriolle A, Grimard C, Zannad N, Babuty D. Antiar-rhythmic effect of statin therapy and atrial fibrillation a meta-analysis of rando-mized controlled trials. J Am Coll Cardiol 2008;51:828–835.9. Rahimi K, Emberson J, McGale P, Majoni W, Merhi A, Asselbergs FW, Krane V,Macfarlane PW. Effect of statins on atrial fibrillation: collaborative meta-analysisof published and unpublished evidence from randomised controlled trials. BMJ2011;342:d1250.10. Wanahita N, Chen J, Bangalore S, Shah K, Rachko M, Coleman CI, Schweitzer P.The effect of statin therapy on ventricular tachyarrhythmias: a meta-analysis. AmJ Ther 2012;19:16–23.11. Rahimi K, Majoni W, Merhi A, Emberson J. Effect of statins on ventricular tachyar-rhythmia, cardiac arrest, and sudden cardiac death: a meta-analysis of publishedand unpublished evidence from randomized trials. Eur Heart J 2012;33:1571–1581.12. Arzamendi D, Benito B, Tizon-Marcos H, Flores J, Tanguay JF, Ly H, Doucet S,LeDuc L, Leung TK, Campuzano O, Iglesias A, Talajic M, Brugada R. Increase insudden death from coronary artery disease in young adults. Am Heart J 2011;161:574–580.13. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP,Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement forreporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Ann Intern Med 2009;151:W65–W94.Editorial1552

Statins: pleiotropic, but less than previously thought

Alain J. Nordmann

Matthias Briel

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EDITORIAL Statins: pleiotropic, but less than previously thought

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Statins: pleiotropic, but less than previously thought

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