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8072 Melrose Ave Los Angeles, CA 90046 +1 (323) 591-1514
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Pilsudskiego 13 Wroclaw, Poland 50-047 +48 71 786 40 71HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis - Palmer - 2014 - The Cochrane Library - Wiley Online Library
BackgroundCardiovascular disease (CVD) is the most frequent cause of death in people with early stages of chronic kidney disease (CKD), for whom the absolute risk of cardiovascular events is similar to people who have existing coronary artery disease. This is an update of a review published in 2009, and includes evidence from 27 new studies (25,068 participants) in addition to the 26 studies (20,324 participants) and excludes three previously included studies (107 participants). This updated review includes 50 studies (45,285 participants); of these 38 (37,274 participants) were meta-analysed.ObjectivesTo evaluate the benefits (such as reductions in all-cause and cardiovascular mortality, major cardiovascular events, MI and slow progression of CKD to end-stage kidney disease (ESKD)) and harms (muscle and liver dysfunction, withdrawal, and cancer) of statins compared with placebo, no treatment, standard care or another statin in adults with CKD who were not on dialysis.Search methodsWe searched the Cochrane Renal Group's Specialised Register to 5 June 2012 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.Selection criteriaRandomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or other statins, on mortality, cardiovascular events, kidney function, toxicity, and lipid levels in adults with CKD not on dialysis were the focus of our literature searches.Data collection and analysisTwo or more authors independently extracted data and assessed study risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes (lipids, creatinine clearance and proteinuria) and risk ratio (RR) for dichotomous outcomes (major cardiovascular events, all-cause mortality, cardiovascular mortality, fatal or non-fatal myocardial infarction (MI), fatal or non-fatal stroke, ESKD, elevated liver enzymes, rhabdomyolysis, cancer and withdrawal rates) with 95% confidence intervals (CI).Main resultsWe included 50 studies (45,285 participants): 47 studies (39,820 participants) compared statins with placebo or no treatment and three studies (5547 participants) compared two different statin regimens in adults with CKD who were not yet on dialysis. We were able to meta-analyse 38 studies (37,274 participants).The risk of bias in the included studies was high. Seven studies comparing statins with placebo or no treatment had lower
and were conducted according to published protocols, outcomes were adjudicated by a committee, specified outcomes were reported, and analyses were conducted using intention-to-treat methods. In placebo or no treatment controlled studies, adverse events were reported in 32 studies (68%) and systematically evaluated in 16 studies (34%).Compared with placebo, statin therapy consistently prevented major cardiovascular events (13 studies, 36,033 RR 0.72, 95% CI 0.66 to 0.79), all-cause mortality (10 studies, 28,276 RR 0.79, 95% CI 0.69 to 0.91), cardiovascular death (7 studies, 19,059 RR 0.77, 95% CI 0.69 to 0.87) and MI (8 studies, 9018 RR 0.55, 95% CI 0.42 to 0.72). Statins had uncertain effects on stroke (5 studies, 8658 RR 0.62, 95% CI 0.35 to 1.12).Potential harms from statin therapy were limited by lack of systematic reporting and were uncertain in analyses that had few events: elevated creatine kinase (7 studies, 4514 RR 0.84, 95% CI 0.20 to 3.48), liver function abnormalities (7 studies, RR 0.76, 95% CI 0.39 to 1.50), withdrawal due to adverse events (13 studies, 4219 RR 1.16, 95% CI 0.84 to 1.60), and cancer (2 studies, 5581 RR 1.03, 95% CI 0.82 to 130).Statins had uncertain effects on progression of CKD. Data for relative effects of intensive cholesterol lowering in people with early stages of kidney disease were sparse. Statins clearly reduced risks of death, major cardiovascular events, and MI in people with CKD who did not have CVD at baseline (primary prevention).Authors' conclusionsStatins consistently lower death and major cardiovascular events by 20% in people with CKD not requiring dialysis. Statin-related effects on stroke and kidney function were found to be uncertain and adverse effects of treatment are incompletely understood. Statins have an important role in primary prevention of cardiovascular events and mortality in people who have CKD.Inhibiteurs de la r&ductase CoA HMG (statines) pour les individus atteints d'une maladie r&nale chronique ne requ&rant pas de dialyseContexteLes maladies cardiovasculaires (MCV) sont la premi&re cause de d&c&s chez les personnes aux premiers stades de l'insuffisance r&nale chronique (IRC), pour lesquelles le risque absolu d'&v&nements cardiovasculaires est semblable & celui des patients atteints de pathologies coronariennes existantes. Cette mise & jour d'une revue publi&e en 2009 inclut des preuves issues de 27 nouvelles &tudes (25&068 participants) en plus des 26 &tudes (20&324 participants) &valu&es pr&c&demment et exclut trois &tudes pr&c&demment incluses (107 participants). Cette revue mise & jour comprend 50 &tudes (45&285 participants), dont 38 (37&274 participants) ont fait l'objet d'une m&ta-analyse.Objectifs&Evaluer les avantages (tels que des r&ductions dans la mortalit& toutes causes ou cardiovasculaire, les &v&nements cardiovasculaires majeurs, l'infarctus du myocarde et l'AVC&; et le ralentissement de la progression de l'IRC vers l'insuffisance r&nale terminale (IRT)) et les inconv&nients (dysfonctionnement musculaire et h&patique, arr&t du traitement et cancer) des statines par rapport au placebo, & l'absence de traitement, aux soins habituels ou & une autre statine chez les adultes atteints d'IRC qui ne sont pas sous dialyse.Strat&gie de recherche documentaireNous avons effectu& des recherches dans le registre sp&cialis& du groupe Cochrane sur la n&phrologie jusqu'au 5 juin 2012 en prenant contact avec le coordinateur des recherches d'essais et en utilisant des termes de recherche pertinents pour cette revue.Crit&res de s&lectionNos recherches documentaires visaient les essais contr&l&s randomis&s (ECR) et les quasi-ECR comparant les effets des statines & un placebo, & l'absence de traitement, aux soins standard ou & d'autres statines, en termes de mortalit&, d'&v&nements cardiovasculaires, de fonction r&nale, de toxicit& et de taux de lipides chez les adultes atteints d'IRC non dialys&s.Recueil et analyse des donn&esDeux ou plusieurs auteurs ont ind&pendamment extrait les donn&es et &valu& les risques de biais des &tudes. Les effets th&rapeutiques ont &t& exprim&s en diff&rences moyennes (DM) pour les r&sultats continus (lipides, clairance de la cr&atinine et prot&inurie) et en risques relatifs (RR) pour les r&sultats dichotomiques (&v&nements cardiovasculaires majeurs, mortalit& toutes causes, mortalit& cardiovasculaire, infarctus du myocarde (IM) fatal ou non fatal, accident vasculaire c&r&bral (AVC) fatal ou non fatal, IRT, &l&vation des enzymes h&patiques, rhabdomyolyse, cancer et taux d'abandon) avec des intervalles de confiance (IC) & 95&%.R&sultats principauxNous avons inclus 50 &tudes (45&285 participants)&: 47 d'entre elles (39&820 participants) comparaient des statines & un placebo ou & l'absence de traitement et trois &tudes (5&547 participants) comparaient deux sch&mas th&rapeutiques diff&rents pour l'administration de statines chez les adultes atteints d'IRC qui n'&taient pas encore sous dialyse. Nous avons pu effectuer une m&ta-analyse de 38 &tudes (37&274 participants).Le risque de biais dans les &tudes incluses &tait &lev&. Sept &tudes comparant les statines & un placebo ou & l'absence de traitement avaient dans l'ensemble un risque de biais plus faible&; ces &tudes &taient r&alis&es selon des protocoles publi&s, leurs r&sultats &taient examin&s par un comit&, les r&sultats sp&cifi&s y &taient rapport&s et les analyses &taient effectu&es en utilisant des m&thodes en intention de traiter. Parmi les &tudes contr&l&es contre placebo ou l'absence de traitement, les &v&nements ind&sirables ont &t& rapport&s dans 32 &tudes (68&%) et syst&matiquement &valu&s dans 16 &tudes (34&%).Comparativement au placebo, le traitement par statines a montr& un effet coh&rent dans la pr&vention des &v&nements cardiovasculaires majeurs (13 &tudes, 36&033 participants&; RR 0,72, IC & 95&% de 0,66 & 0,79), de la mortalit& toutes causes confondues (10 &tudes, 28&276 participants&; RR 0,79, IC & 95&% de 0,69 & 0,91), des d&c&s d'origine cardiovasculaire (7 &tudes, 19&059 participants&; RR 0,77, IC & 95&% de 0,69 & 0,87) et de l'IM (8 &tudes, 9&018 RR 0,55, IC 95% 0,42 & 0,72). Les statines avaient des effets incertains sur l'AVC (5 &tudes, 8&658 participants&; RR 0,62, IC & 95&% de 0,35 & 1,12).Les &ventuels inconv&nients du traitement par statines ont &t& limit&s par le manque de compte-rendus syst&matiques et &taient incertains dans les analyses avec de rares &v&nements&: &levation de la cr&atine kinase (7 &tudes, 4&514 participants&; RR 0,84, IC & 95&% de 0,20 & 3,48), anomalies de la fonction h&patique (7 &tudes, RR 0,76, IC & 95&% de 0,39 & 1,50), abandon en raison d'&v&nements ind&sirables (13 &tudes, 4&219 participants&; RR 1,16, IC & 95&% de 0,84 & 1,60) et cancer (2 &tudes, 5&581 participants&; RR 1,03, IC & 95&% de 0,82 & 130).Les statines avaient des effets incertains sur la progression de l'IRC. Les donn&es concernant les effets relatifs de diminution importante du cholest&rol chez les personnes aux premiers stades de l'insuffisance r&nale &taient rares. Les statines r&duisaient clairement les risques de d&c&s, d'&v&nements cardiovasculaires majeurs et d'IM chez les personnes atteintes d'IRC sans MCV & l'inclusion (pr&vention primaire).Conclusions des auteursLes statines r&duisaient de fa&on coh&rente les d&c&s et les &v&nements cardiovasculaires majeurs de 20&% chez les personnes atteintes d'IRC non dialys&es. Sur l'AVC et la fonction h&patique, les effets li&s aux statines &taient impr&cis et les effets ind&sirables du traitement sont encore mal compris. Les statines ont un r&le important dans la pr&vention primaire des &v&nements cardiovasculaires et de la mortalit& chez les personnes atteintes d'IRC.Estatinas (inibidores da HMG-CoA redutase) para pessoas com doen&a renal cr&nica, sem necessidade de di&liseIntrodu&&oA doen&a cardiovascular & a principal causa de morte das pessoas com doen&a renal cr&nica (DRC) em est&gio inicial. Essas pessoas t&m um risco absoluto de eventos cardiovasculares que & semelhante ao daquelas que t&m doen&a coronariana preexistente. Esta & a atualiza&&o de uma revis&o publicada originalmente em 2009 e inclui os resultados de 27 novos estudos (25.068 participantes), al&m dos 26 estudos j& inclu&dos anteriormente (20.324 participantes); e exclui tr&s estudos anteriormente inclu&dos (107 participantes). Esta atualiza&&o inclui, portanto, um total de 50 estudos (45.285 participantes), sendo que 38 estudos (37.274 participantes) foram inclu&dos em metan&lises.ObjetivosAvaliar os benef&cios e efeitos adversos das estatinas comparadas com placebo, com aus&ncia de tratamento, com o tratamento padr&o ou com outras estatinas em adultos com doen&a renal cr&nica que n&o estejam em di&lise. Os benef&cios avaliados foram, por exemplo, redu&&o de mortalidade cardiovascular por todas as causas, eventos cardiovasculares maiores, infarto do mioc&rdio e derrame e progress&o lenta para doen&a renal cr&nica. Os efeitos adversos ou danosos foram disfun&&o muscular e hep&tica, retirada e c&ncer.M&todos de buscaFizemos buscas no Cochrane Renal Group&s Register at& 5 de junho de 2012, usando termos relevantes para esta revis&o.Crit&rio de sele&&oEnsaios cl&nicos randomizados (ECR) e quasi-randomizados compararam os efeitos das estatinas versus placebo, nenhum tratamento, tratamento padr&o ou outras estatinas, na mortalidade, nos eventos cardiovasculares, na fun&&o renal, na toxicidade e nos n&veis dos lip&dios em adultos com IRC sem di&lise.Coleta dos dados e an&lisesDois ou mais revisores extra&ram independentemente os dados e avaliaram o risco de vi&s dos estudos. Para os desfechos cont&nuos (lip&dios, creatinina e protein&ria), apresentamos os resultados como diferen&a m&dia (MD). Apresentamos como risco relativo (RR) com intervalos de confian&a (IC) de 95% os resultados dos desfechos dicot&micos: eventos cardiovasculares, mortalidade geral, mortalidade cardiovascular, infarto do mioc&rdio (IM) fatal ou n&o fatal, acidente vascular cerebral fatal ou n&o fatal, IRC terminal aumento das enzimas hep&ticas, rabdomi&lise, c&ncer e taxa de abandono da medica&&o.Principais resultadosForam inclu&dos 50 estudos (45.285 participantes): 47 estudos (39.820 participantes) comparando as estatinas com placebo ou nenhum tratamento e tr&s estudos (5.547 participantes) comparando dois regimes diferentes de estatinas em adultos com DRC sem di&lise. Foi poss&vel fazer metan&lises com 38 estudos (37.274 participantes).O risco de vi&s dos estudos inclu&dos foi alto. Sete estudos comparando as estatinas com placebo ou nenhum tratamento tiveram menor risco de vi&s global. Esses estudos foram conduzidos de acordo com os protocolos publicados, os desfechos foram julgados por um comit&, os desfechos especificados foram relatados e as an&lises foram realizadas conforme &inten&&o de tratar&. Nos estudos em que o grupo controle recebeu placebo ou nenhum tratamento, os efeitos adversos foram relatados em 32 estudos (68%) e sistematicamente avaliados em 16 estudos (34%).Em compara&&o com placebo, o uso das estatinas preveniu a ocorr&ncia de eventos cardiovasculares (13 estudos, 36.033 RR 0,72, IC 95% 0,66 a 0,79), a mortalidade global (10 estudos, 28.276 RR 0,79, IC 95% 0,69 a 0,91), mortalidade de causa cardiovascular (7 estudos, 19.059 RR 0,77, IC 95% 0,69 a 0,87) e infarto (8 estudos, 9.018 RR 0,55, IC 95% 0,42 a 0,72). O efeito das estatinas sobre a taxa de acidente vascular cerebral n&o foi significativo (5 estudos, 8.658 RR 0,62, IC 95% 0,35 a 1,12).A falta de descri&&o sistem&tica dos eventos adversos relacionados ao uso das estatinas limitou nossa avalia&&o desse desfecho. Nos estudos que relataram esse desfecho, os eventos adversos foram raros e isso prejudicou sua avalia&&o: aumento da creatinino-quinase (CPK) (7 estudos, 4.514 RR 0,84, IC 95% 0,20 a 3,48), altera&&o da fun&&o hep&tica (7 estudos, RR 0,76, IC 95% 0,39 a 1,50), abandono do tratamento devido a eventos adversos (13 estudos, 4.219 RR 1,16, IC 95% 0,84 a 1,60) e c&ncer (2 estudos, 5.581 RR 1,03, IC 95% 0,82 a 130).O efeito das estatinas sobre a progress&o da DRC foi inconsistente. Houve poucos dados sobre os efeitos relativos da redu&&o intensiva de colesterol em pessoas em est&gios iniciais da doen&a renal. O uso das estatinas produziu uma redu&&o consistente do risco de mortalidade, eventos cardiovasculares maiores e infarto em pessoas com DRC sem doen&a cardiovascular preexistente (preven&&o prim&ria).Conclus&o dos autoresEm pessoas com DRC que n&o precisam de di&lise, o uso de estatinas reduz em 20% os riscos de morte e de eventos cardiovasculares maiores. Os efeitos das estatinas sobre o acidente vascular cerebral e a fun&&o renal foram inconsistentes. Os efeitos adversos do tratamento com estatinas para esse tipo de paciente ainda n&o est&o claros. As estatinas t&m um papel importante na preven&&o prim&ria de eventos cardiovasculares e na taxa de mortalidade em pessoas com DRC.Inhibidores de la HMG CoA reductasa (estatinas) para pacientes con nefropat&as cr&nicas que no que requieren di&lisisAntecedentesLas enfermedades cardiovasculares (EC) son la causa m&s frecuente de muerte en pacientes con nefropat&a cr&nica (NC) en estadio inicial, para quienes el riesgo absoluto de eventos cardiovasculares es similar al de los pacientes que padecen una arteriopat&a coronaria existente. &Esta es una actualizaci&n de una revisi&n publicada en 2009, que incluye pruebas de 27 nuevos estudios (25 068 participantes), adem&s de los 26 estudios (20 324 participantes) e y excluye tres estudios incluidos anteriormente (107 participantes). Esta revisi&n actualizada incluye 50 estudios (45 285 participantes); de &stos, 38 (37 274 participantes) fueron metanalizados.ObjetivosEvaluar los efectos beneficiosos (como las reducciones en la mortalidad por todas las causas y la mortalidad cardiovascular, los eventos cardiovasculares graves, el IM y el accid y la progresi&n lenta de la NC hacia una insuficiencia renal terminal [IRT]) y perjudiciales (disfunci&n muscular y hep&tica, retiros y c&ncer) de las estatinas comparadas con placebo, ning&n tratamiento, atenci&n est&ndar u otras estatinas en adultos con NC que no reciben di&lisis.M&todos de b&squedaSe realizaron b&squedas en el registro especializado del Grupo Cochrane de Ri&&n (Cochrane Renal Group) hasta el 5 de junio de 2012, mediante contacto con el coordinador de b&squeda de ensayos, utilizando t&rminos de b&squeda relevantes para esta revisi&n.Criterios de selecci&nLas b&squedas bibliogr&ficas se centraron en los ensayos controlados aleatorios (ECA) y los ensayos controlados cuasialeatorios que compararon los efectos de las estatinas con placebo, ning&n tratamiento, atenci&n est&ndar, u otras estatinas, en lo que respecta a la mortalidad, los eventos cardiovasculares, la funci&n renal, la toxicidad y los niveles de l&pidos en adultos con NC que no reciben di&lisis.Obtenci&n y an&lisis de los datosDos o m&s autores, de forma independiente, extrajeron los datos y evaluaron el riesgo de sesgo de los estudios. Los efectos del tratamiento se expresaron como diferencia de medias (DM) para los resultados continuos (l&pidos, depuraci&n de creatinina y proteinuria) y como cociente de riesgos (CR) para los resultados dicot&micos (eventos cardiovasculares graves, mortalidad por todas las causas, mortalidad cardiovascular, infarto de miocardio [IM] mortal o no mortal, accidente cerebrovascular mortal o no mortal, IRT, enzimas hep&ticas elevadas, rabdomi&lisis, c&ncer y tasas de retiros) con intervalos de confianza (IC) del 95%.Resultados principalesSe incluyeron 50 estudios (45 285 participantes): 47 estudios (39 820 pacientes) compararon estatinas con placebo o ning&n tratamiento y tres estudios (5547 pacientes) compararon dos reg&menes diferentes de estatinas en adultos con NC que todav&a no hab&an recibido di&lisis. Fue posible metanalizar 38 estudios (37 274 participantes).El riesgo de sesgo de los estudios incluidos era alto. Siete estudios que compararon estatinas con placebo o ning&n tratamiento presentaron un riesgo de sesgo menor en general, y se realizaron seg&n los protocolos publicados, los resultados fueron adjudicados por un comit&, se informaron los resultados definidos y se realizaron los an&lisis mediante m&todos de intenci&n de tratar. En los estudios controlados con placebo o ning&n tratamiento, los eventos adversos se informaron en 32 estudios (68%) y en 16 estudios (34%) fueron evaluados de forma sistem&tica.En comparaci&n con el placebo, el tratamiento con estatinas previno de forma consistente los eventos cardiovasculares graves (13 estudios, 36 033 CR 0,72; IC del 95%: 0,66 a 0,79) la mortalidad por todas las causas (10 estudios, 28 276 CR 0,79; IC del 95%: 0,69 a 0,91), la mortalidad cardiovascular (7 estudios, 19 059 CR 0,77; IC del 95%: 0,69 a 0,87) y el IM (8 estudios, 9018 CR 0,55; IC del 95%: 0,42 a 0,72). Las estatinas tuvieron efectos inciertos sobre el accidente cerebrovascular (5 estudios, 8658 CR 0,62; IC del 95%: 0,35 a 1,12).Los efectos perjudiciales potenciales del tratamiento con estatinas fueron limitados por la falta de un informe sistem&tico y fueron inciertos en los an&lisis que tuvieron pocos eventos: creatinquinasa elevada (7 estudios, 4514 CR 0,84; IC del 95%: 0,20 a 3,48), anomal&as de la funci&n hep&tica (7 estudios, CR 0,76; IC del 95%: 0,39 a 1,50), retiros debido a los eventos adversos (13 estudios, 4219 CR 1,16; IC del 95%: 0,84 a 1,60) y c&ncer (2 estudios, 5581 CR 1,03; IC del 95%: 0,82 a 130).Las estatinas tuvieron efectos inciertos sobre la progresi&n de la NC. Los datos sobre los efectos relativos de la disminuci&n intensiva del colesterol en pacientes con nefropat&a cr&nica en estadio inicial fueron dispersos. Las estatinas redujeron claramente los riesgos de muerte, eventos cardiovasculares graves e IM en pacientes con NC que no presentaban EC al inicio (prevenci&n primaria).Conclusiones de los autoresLas estatinas reducen de forma consistente la muerte y los eventos cardiovasculares graves en un 20% en pacientes con NC que no requieren di&lisis. Se encontraron efectos inciertos relacionados con las estatinas sobre el accidente cerebrovascular y la funci&n renal y los efectos adversos del tratamiento no se conocen por completo. Las estatinas tienen una funci&n importante en la prevenci&n primaria de los eventos cardiovasculares y la mortalidad en los pacientes con NC.Statins can help reduce risk of death in people with chronic kidney disease who do not need dialysisAdults with chronic kidney disease (CKD) have high risks of developing complications from heart disease.&It is thought that statin treatment lowers cholesterol and reduces risk of death and complications from heart disease.We looked at 50 studies published before June 2012 concerning statin treatment in over 45,000 people with CKD who did not need dialysis treatment. We found that statins reduced the risk of death and major heart-related events by 20%. Statin treatment was also found to be effective in reducing cardiac disease and death in people who have CKD but not heart disease. In these people, statin treatment reduced risks of heart attack by half.Statins have some potential harmful effects on liver and muscle function, and some cancers. We found that these issues were not analysed well in the studies we evaluated, and these effects are not well understood.Although use of statins did not clearly reduce risks of kidney disease progression, they can be recommended to reduce risks of death and heart-related events in people with early stages of kidney disease. However, the potential side-effects are uncertain, and need further study.Les statines peuvent aider & r&duire le risque de d&c&s chez les personnes atteintes d'insuffisance r&nale chronique qui ne n&cessitent pas de dialyseLes adultes atteints d'insuffisance r&nale chronique (IRC) ont un risque &lev& de d&velopper des complications de maladie cardiaque.On pense que le traitement par statines diminue le cholest&rol et r&duit les risques de d&c&s et de complications de maladie cardiaque.Nous avons examin& 50 &tudes publi&es avant juin 2012 concernant le traitement par statines chez plus de 45&000 personnes atteintes d'IRC qui n'avaient pas besoin d'un traitement de dialyse. Nous avons constat& que les statines r&duisaient les risques de d&c&s et d'&v&nements cardiaques majeurs de 20&%. Le traitement par statines s'est &galement av&r& efficace dans la r&duction des maladies et des d&c&s cardiaques chez les personnes atteintes d'IRC sans maladie cardiaque. Chez ces personnes, le traitement par statines r&duit les risques de crise cardiaque de moiti&.Les statines ont de potentiels effets nocifs sur la fonction h&patique et musculaire ainsi que sur certains cancers. Nous avons constat& que ces questions n'&taient pas bien analys&es dans les &tudes que nous avons &valu&es, et ces effets ne sont pas bien compris.Bien que l'utilisation des statines n'ait pas r&duit clairement les risques de progression de l'insuffisance r&nale, elles peuvent &tre recommand&es pour r&duire les risques de d&c&s et d'&v&nements cardiaques chez les personnes qui sont aux premiers stades de l'insuffisance r&nale. Cependant, les effets secondaires potentiels sont incertains et doivent &tre davantage &tudi&s.Notes de traductionTraduction r&alis&e par le Centre Cochrane Fran&aisEstatinas podem ajudar a reduzir o risco de morte em pessoas com doen&a renal cr&nica que n&o precisam de di&liseAdultos com doen&a renal cr&nica (DRC) t&m alto risco de desenvolver complica&&es decorrentes de doen&as do cora&&o (doen&as card&acas).&Acredita-se que o tratamento dessas pessoas com estatinas reduz o seu colesterol e o risco de elas morrerem e de terem complica&&es card&acas.Avaliamos 50 estudos publicados antes de junho de 2012 a respeito do uso de estatinas em mais de 45.000 pessoas com DRC que n&o precisavam de di&lise. Conclu&mos que as estatinas reduziram em 20% o risco de morte e de problemas card&acos graves nessas pessoas. O tratamento com estatina tamb&m mostrou ser eficaz na redu&&o de doen&a card&aca e na diminui&&o da mortalidade de pessoas com DRC que n&o t&m doen&a card&aca. Nessas pessoas, o tratamento com estatina reduziu os riscos de ataque card&aco pela metade.As estatinas podem causar alguns efeitos adversos os m&sculos, no funcionamento do f&gado e propiciar o surgimento de alguns tipos de c&ncer. Descobrimos que essas quest&es n&o foram bem analisadas nos estudos inclu&dos nesta revis&o e, portanto, esses efeitos ainda n&o est&o claros.Embora as estatinas n&o reduzam a progress&o da doen&a renal, elas s&o recomendadas para reduzir os riscos de morte e eventos card&acos nas pessoas com doen&a renal em est&gio inicial. No entanto, os poss&veis efeitos colaterais desse rem&dio ainda s&o incertos e precisam ser melhor estudados.Notas de tradu&&oTradu&&o do Centro Cochrane do Brasil (Arnaldo Alves da Silva). Contato: tradutores@centrocochranedobrasil.org.brLas estatinas pueden ayudar a reducir el riesgo de muerte en pacientes con nefropat&a cr&nica que no necesitan di&lisisLos adultos con nefropat&a cr&nica (NC) presentan un riesgo alto de desarrollar complicaciones relacionadas con cardiopat&as. Se cree que el tratamiento con estatinas reduce el colesterol y disminuye el riesgo de muerte y las complicaciones relacionadas con cardiopat&as.Se revisaron 50 estudios publicados antes de junio de 2012 relacionados con el tratamiento con estatinas en m&s de 45 000 pacientes con NC que no necesitaban tratamiento con di&lisis. Se encontr& que las estatinas redujeron el riesgo de muerte y los eventos card&acos graves en un 20%. Tambi&n se encontr& que el tratamiento con estatinas fue efectivo para reducir las enfermedades card&acas y la muerte en pacientes con NC, pero que no presentan cardiopat&a. En dichos pacientes, el tratamiento con estatinas redujo los riesgos de un ataque card&aco a la mitad.Las estatinas presentan algunos efectos perjudiciales potenciales sobre la funci&n hep&tica y muscular y algunos tipos de c&ncer. Se encontr& que estos temas no se analizaron de forma adecuada en los estudios que se evaluaron, y que estos efectos no se comprenden bien.Aunque la administraci&n de estatinas no redujo claramente los riesgos de progresi&n de la nefropat&a, pueden recomendarse para reducir los riesgos de muerte y eventos card&acos en pacientes con nefropat&a en estadio inicial. Sin embargo, los posibles efectos secundarios son inciertos y requieren mayor estudio.Notas de traducci&nLa traducci&n y edici&n de las revisiones Cochrane han sido realizadas bajo la responsabilidad del Centro Cochrane Iberoamericano, gracias a la suscripci&n efectuada por el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno espa&ol. Si detecta alg&n problema con la traducci&n, por favor, contacte con Infoglobal Suport, cochrane@infoglobal-suport.com.Summary of findings()Summary of findings&for the main comparison.& Statin versus placebo or no treatment for adults with chronic kidney disease not on dialysis Patient or population: adults with chronic kidney disease
Settings: not on dialysis
Intervention: statin
Comparison: placebo or no treatment OutcomesIllustrative comparative risks* (95% CI)Relative effect (95% CI)No of participants (studies)Quality of the evidence (GRADE)Assumed riskCorresponding risk per year treatedPlacebo or no treatmentStatins Major cardiovascular events 20 per 1000 14 per 1000
(13 to 16 per 1000) 6 fewer (4 to 7 fewer)
RR 0.72 (0.66 to 0.79)36,033 (13)&&&&
high All-cause mortality 25 per 1000 20 per 1000
(17 to 23 per 1000) 5 fewer (2 to 8 fewer)
RR 0.79 (0.69 to 0.91)28,276 (10)&&&&
high Cardiovascular mortality 15 per 1000 12 per 1000 (10 to 13 per 1000) 3 fewer (2 to 5 fewer)
RR 0.77 (0.69 to 0.87)19,059 (7)&&&⊝
moderate*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: C RR: Risk RatioGRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimateBackgroundDescription of the conditionThe global incidence and prevalence of chronic kidney disease (CKD) is increasing (; ). More than 13% of people aged 20 years and over in the United States have CKD due in part to epidemics of obesity, high blood pressure and diabetes (). Overall, cardiovascular deaths (both related to myocardial infarction (MI) and cardiac arrhythmias) account for over 50% of deaths in people with severe kidney disease on chronic dialysis (). Similarly, a large proportion of people with earlier stages of kidney disease die of cardiovascular disease before they develop end-stage kidney disease (ESKD) (). People with CKD not on dialysis have risks of death or complications from cardiovascular disease that are equivalent to people with existing heart disease (; ).How the intervention might workMany traditional and non-traditional cardiovascular risk factors are prevalent in people with CKD (; ). Elevated serum cholesterol and triglycerides are present in 60% of people with CKD and an even higher proportion of people who have nephrotic syndrome (). Abnormal lipid levels may contribute to the development of cardiovascular disease (CVD) and initiation and progression of CKD (; ). In the Atherosclerosis Risk in Communities Study (ARIC) and Physicians Health study, elevated lipid levels were associated with lower kidney function (). Apart from their lipid lowering function, it is plausible that statin use may result in improved kidney function by decreasing urinary protein excretion and inflammation and reducing fibrosis of tubular cells (). Statins could reduce kidney disease progression and incidence of CVD in people with kidney dysfunction ().Clinical studies in people with CVD or who are at risk of developing CVD have shown that statins safely reduce the five year incidence of death or major cardiovascular events by about 20% ().Why it is important to do this reviewIn our previous review, our meta-analysis showed that statins proportionally reduced risks of death by about 20% in people with CKD and lowered proteinuria by approximately 750 mg over 24 hours, although risks of adverse events (muscle or liver damage) were uncertain ().New data from
and post hoc analyses in subgroups of people with CKD in larger studies have become available since our last review was published in 2009 (; ; ; ; ). In 2011, an advisory committee that considered data from the Study of Heart and Renal Protection study () voted to recommend the use of simvastatin or ezetimibe or both for people with CKD not on dialysis ().In light of additional study data and active policy debate, we updated our 2009 review to evaluate the benefits and harms of statins in people with CKD not on dialysis.ObjectivesTo evaluate the benefits (such as reductions in all-cause and cardiovascular mortality, major cardiovascular events, MI and slow progression of CKD to ESKD) and harms (muscle and liver dysfunction, withdrawal, and cancer) of statins compared with placebo, no treatment, standard care or another statin in adults with CKD who were not on dialysis.MethodsCriteria for considering studies for this reviewTypes of studiesRCTs and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) that evaluated the benefits and harms of statins in adults with CKD who were not on dialysis. The first periods of randomised cross-over studies were included. We excluded studies of fewer than eight weeks duration. Such studies were unlikely to enable detection of mortality or cardiovascular outcomes related to statin therapy ().Types of participantsInclusion criteriaStudies enrolling adults with CKD (defined and staged according to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines) () who were not on dialysis. This included people with persistent urine abnormalities (proteinuria or albuminuria) or structural kidney disease with normal kidney function (such as polycystic kidney disease). Studies were included irrespective of whether participants had CVD at baseline.Exclusion criteriaStudies of adults with CKD on dialysis (peritoneal dialysis or haemodialysis) and kidney transplant recipients were excluded. These populations have been specifically reviewed in other Cochrane reviews (; ).Types of interventionsWe included studies that compared statins with placebo, no treatment or standard care, or another statin. We excluded studies where a statin was compared with a second non-statin regimen including fibrate therapy.Types of outcome measuresPrimary outcomesMajor cardiovascular eventsAll-cause mortalityCardiovascular mortalityFatal and non-fatal MIFatal and non-fatal strokeESKDAdverse events attributable to intervention Elevated creatine kinaseElevated liver enzymesWithdrawal due to adverse eventsCancer. Secondary outcomesEnd of treatment creatinine clearance (CrCl) or glomerular filtration rate (GFR) (any measure)End of treatment proteinuria (micro or macroalbuminuria)Serum lipid levels Total cholesterolLow density lipoprotein (LDL) cholesterolHigh density lipoprotein (HDL) cholesterolTriglycerides. Search methods for identification of studiesElectronic searchesWe searched the Cochrane Renal Group's Specialised Register to 5 June 2012 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. The Cochrane Renal Group&s Specialised Register contains studies identified from the following sources.Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)Weekly searches of MEDLINE OVID SPHandsearching of renal-related journals and the proceedings of major renal conferencesSearching of the current year of EMBASE OVID SPWeekly current awareness alerts for selected renal journalsSearches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of the Cochrane Renal Group. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about the .See
for search terms used in strategies for this review.Searching other resourcesReference lists of clinical practice guidelines, review articles and relevant studies.Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.Data collection and analysis2009 reviewThe 2009 review was undertaken by eight authors (SDN, FP, CM, DJ, FP, VP, JC, GFMS). The search strategy described was used to obtain titles and abstracts of studies relevant to the review. Titles and abstracts were screened independently by two authors (SDN, FP) who excluded studies that did not meet our Inclusion criteria. However, studies and reviews that might include relevant data or information on relevant studies were retained initially. The same two authors independently assessed retrieved abstracts, and if necessary the full text, of these studies to determine which studies satisfied the inclusion criteria. Data extraction was carried out by the same authors independently using standard data extraction forms. Studies reported in non-English language journals were translated before assessment. When more than one publication of one study existed, only the publication with the most complete data was included. Any further information required from study authors was requested and relevant information obtained was included in the review. Disagreements were resolved in consultation with a third author (GFMS).Selection of studiesFor our 2013 update, the search strategy described was used to obtain titles and abstracts of studies relevant to the review. Titles and abstracts were screened independently by the authors, who discarded studies that however, studies and reviews thought to potentially include relevant data or information on studies was retained initially. The authors independently assessed retrieved abstracts, and the full text where necessary, to determine which studies satisfied our inclusion criteria. Disagreements between authors were resolved in consultation with a third author.Data extraction and managementData extraction was carried out independently by three authors using standard data extraction forms. Studies reported in non-English language journals were translated before assessment. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses. Where relevant outcomes were only published in earlier versions, these data were used. Any discrepancies between published versions were highlighted.Assessment of risk of bias in included studiesThe following items were independently assessed by two authors using the risk of bias assessment tool () ().Was there adequate sequence generation (selection bias)?Was allocation adequately concealed (selection bias)?Was knowledge of the allocated interventions adequately prevented during the study (detection bias)? Participants and personnelOutcome assessors Were incomplete outcome data adequately addressed (attrition bias)?Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?Was the study apparently free of other problems that could put it at a risk of bias?Measures of treatment effectFor dichotomous outcomes (cardiovascular events, mortality, elevated liver enzymes, rhabdomyolysis, withdrawal rates and cancer) results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (lipid parameters, proteinuria, CrCl), the mean difference (MD) was used, or the standardised mean difference (SMD) where different scales were used.Dealing with missing dataAny further information required from the original author was requested and relevant information was included in the review. Evaluation of important numerical data such as screened, randomised patients as well as intention-to-treat, as-treated and per-protocol population was performed carefully. Attrition rates, such as drop-outs, losses to follow-up and withdrawals, were investigated. Issues of missing data and imputation methods (for example, last observation carried forward) were critically appraised ().Assessment of heterogeneityHeterogeneity was analysed using a Chi² test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I² test (). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.Assessment of reporting biasesTo assess potential bias from small-study effects, we constructed funnel plots for the log risk ratio in individual studies against the standard error of the risk ratio. We carried out formal statistical assessment of funnel plot asymmetry with the Egger regression test (). We conducted analyses using Comprehensive Meta-Analysis (Version 2, Biostat, Englewood, NJ, 2005).Data synthesisWe summarised the quality of the evidence together with the absolute treatment effects based on estimated baseline risks using Grading of Recommendations Assessment Development and Evaluation (GRADE) guidelines (). Absolute numbers of people with cardiovascular or adverse events avoided or incurred were estimated using the risk estimate for the outcome together with the estimated absolute population risk from previously published observational cohort studies (; ; ).Subgroup analysis and investigation of heterogeneityWe conducted subgroup analyses to explore potential sources of heterogeneity in modifying estimates of the effects of statins in the studies. We planned subgroup analyses according to the following participant, intervention, or study-related characteristics, when subgroups contained four or more independent studies (statin type, statin dose (equivalent to simvastatin, baseline cholesterol (& 230 mg/dL versus & 230 mg/dL), age (& 55 years versus & 55 years), proportion with diabetes (& 20% versus & 20%), or adequacy of allocation concealment. We conducted sensitivity analyses including only studies in which CVD at baseline was an exclusion criterion (primary prevention studies).Sensitivity analysisWe performed sensitivity analyses to explore the influence of the following factors on effect size.Repeating the analysis excluding unpublished studiesRepeating the analysis taking account of risk of biasRepeating the analysis excluding any very long or large studies to establish how much they dominate the resultsRepeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.ResultsDescription of studies2009 reviewWe included 26 studies (25,017 participants) (; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ) in this review for data available at July 2008 ().Results of the search2014 review updateWe removed three studies (107 participants) from our 2009 review because adults with CKD were not included (); data were available in another publication (duplicate publication of ) or the study duration was less than eight weeks duration (). We noted that in the 2009 review, all diabetic participants in the
study were considered included in the review, whereas only 1329 of these participants had CKD. Therefore, data from 23 studies, comprising 20,217 participants were included in the 2014 update from the 2009 review.Electronic database searching in June 2012 identified 2580 citations (). We excluded 662 duplicate records and screened 1918 citations by title and abstract. Of the 1918, we excluded a further 1518 records: 215 were not RCTS; 811 were not in populations with CKD; eight in 441 did
17 were ongoing studies not rel 11 were fewer than
and 15 were not in humans. Therefore, we assessed the full text of 297 reports of 69 potential studies. Four studies were not RCTs; six studies were not conducted in populations of people with CKD who did not require dialysis or were c 12 studies did not compare statin treatment with placebo, no treatme and eight studies were of short duration (& eight weeks).Figure&1. Study flow diagram.*Other - short duration, animal studiesWe included 27 new studies (25,068 participants), 24 studies (19,521 participants) comparing statin with placebo or no treatment (; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ) and three studies (5547 participants) compared two statin regimens (; ; ).Overall, 47 studies (39,738 participants) comparing statin with placebo or no treatment and three studies (5547 participants) comparing statins with another statin were included (50 45,285 participants). There were 11 comparisons (in 10 studies) that provided post hoc data for subgroups of 36,325 adults with CKD within larger studies that compared statins with placebo or no treatment (; ; ; ; ; ; ; ; ; ). Two comparisons provided post hoc data for 5428 adults comparing two statin regimens (; ).We included 38 studies that involved 37,274 adult participants that compared statins with placebo or no treatment in our meta-analyses.Included studiesStatin versus placebo or no treatmentStudies varied in sample size (median 56 range 14 to 1233 participants). There were eight comparisons that included more than 1000 participants (; ; ; ; ; ; ).The median statin dose (equivalent to simvastatin) was 20 mg (range 5 to 80 mg/d). Statin interventions included atorvastatin (; ; ; ; ; ; ; ), cerivastatin (), fluvastatin (; ; ; ; ; ; ; ), lovastatin (; ), pitavastatin (; ; ), pravastatin (; ; ; ; ; ; ; ; ), rosuvastatin (; ; ), simvastatin (; ; ; ; ; ; ; ; ; ; ), simvastatin and ezetimibe (), and simvastatin or pravastatin ().Median follow-up duration was 12 months (range 2 to 66 months). Studies reporting mortality outcomes that could be included in meta-analyses had a median follow-up duration of 47 months (range 5 to 60 months).Although three studies enrolled participants with established acute or stable coronary artery disease (; ; ), 10 studies excluded participants with clinical coronary artery disease (; ; ; ; ; ; ; ; ; ). Median baseline low density lipoprotein cholesterol was 225 mg/dL (range 136 to 390 mg/dL).Eight studies included only participants who had diabetes (; ; ; ; ; ; ; ); and people with diabetes were excluded from seven studies (; ; ; ; ; ; ).
combined outcome data for adults not on dialysis with those on dialysis. Data from this study were included in the meta-analyses.Effects of statins on mortality and adverse events data from
could not be included in analyses because disaggregated data for 6247 adults with CKD were not available.The Pravastatin Pooling Project was a pooled analysis of three large data sets of participants with kidney impairment who were included in three major statin studies (;
) conducted in the general population, and were included as a single comparison ().Statin versus other statin
compared two doses of atorvastatin and
compared simvastatin with atorvastatin. Sample sizes ranged from 119 to 2321 participants. Follow-up for reported outcomes was 25 to 60 months. Baseline LDL cholesterol levels ranged from 131 to 176 mg/dL. Meta-analysis was not possible because three or more studies were not available for each comparison.Excluded studiesSee: Thirty two studies did not meet our eligibility criteria for the following reasons. An analysis of a statin versus placebo, no treatment or another statin was not included (; ; ; ; ; ; ; ; ; ; ; ; ); did not assess treatment effects in patients with CKD not requiring dialysis (; ; ; ); were not RCTs (; ; ; ); included children (; ; ); or provided follow-up of an unclear duration or were fewer than eight weeks (; ; ; ; ; ; ; ; ).Risk of bias in included studiesThe risk of bias in the included studies was high (; ). Seven studies comparing statins with placebo or no treatment had lower
and were conducted according to published protocols, outcomes were adjudicated by a committee, specified outcomes were reported, and analyses were conducted using intention-to-treat methods (; ; ; ; ; ; ). In placebo or no treatment controlled studies, adverse events were reported in 32 studies (68%) and systematically evaluated in 16 studies (34%).Figure&2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studiesFigure&3. Risk of bias summary: review authors' judgements about each risk of bias item for each included studyIn the meta-analysis for major cardiovascular events and death, data were obtained from studies that generally had lower risk of bias than all included studies. In the analysis for major cardiovascular events, random sequence generation was assessed as low risk in 36%, allocation concealment was low risk in 57%, outcome assessors were blinded in 79%, analyses were intention-to-treat in 79%, attrition was low risk in 57%, and 79% reported adverse events systematically.In meta-analyses for death, data were obtained from studies in which sequence generation was assessed as low risk in 27%, allocation concealment was low risk in 55%, outcome assessors were blinded in 73%, complete outcome data/analysis was by intention-to-treat in 73%, attrition was low risk in 45%, and 82% assessed adverse events systematically.AllocationRandom sequence generation was low risk in fewer than 25% of included studies, and allocation concealment was low risk in only 30%.BlindingParticipants and personnel were blinded in 40% of studies, and outcome assessors were blinded in only 25%.Incomplete outcome dataCompleteness of outcome reporting and intention-to-treat analysis methodology was applied in 25% of included studies.Selective reportingWe explored for evidence of publication bias for all-cause mortality, major cardiovascular events, and MI outcomes using the Egger regression test. We found evidence for possible publication bias due to missing studies for risks of major adverse cardiovascular events (Egger P = 0.02). Imputing missing studies using the Duval and Tweedie trim and fill method () imputed no additional studies and did not alter the effect estimate observed. There was no evidence for publication bias in the estimate of treatment effects on MI or all-cause mortality.Other potential sources of biasThe risk of bias due to sources of funding was high in 20%, low in 32% and unclear in 48% of studies.Effects of interventionsSee: Primary outcomesWe found moderate-to-high quality evidence that statin therapy reduced major cardiovascular events ( (13 studies, 36,033 participants): RR 0.72, 95% CI 0.66 to 0.79; I² = 40%), all-cause mortality ( (10 studies, 28,726 participants): RR 0.79, 95% CI 0.69 to 0.91; I² = 32%), and cardiovascular mortality ( (7 studies, 19,059 participants): RR 0.77, 95% CI 0.69 to 0.87; I² = 0% ) ().Statins markedly lowered risk of fatal or non-fatal MI ( (8 studies, 9018 participants): RR 0.55, 95% CI 0.42 to 0.72; I² = 0%) although effects on fatal or non-fatal stroke were uncertain ( (5 studies, 8658 participants): RR 0.63, 95% CI 0.35 to 1.12; I² = 53%). There was no significant heterogeneity in these analyses.
reported statins had little or no effect on progression to ESKD ( (6247 participants): RR 0.98, 95% CI 0.91 to 1.05).Statins had uncertain effects on treatment-related adverse events in analyses that included few events: elevated creatine kinase ( (7 studies, 4514 participants): RR 0.84, 95% CI 0.20 to 3.48; I² = 0%), liver dysfunction ( (7 studies, 7991 participants): RR 0.76, 95% CI 0.39 to 1.50; I² = 0%), withdrawal due to adverse events ( (13 studies, 4219 participants): RR 1.16, 95% CI 0.84 to 1.60; I² = 45%), and cancer ( (2 studies, 5581 participants): RR 1.03, 95% CI 0.82 to 1.30; I² = 0%). The analysis for withdrawal due to adverse events had evidence for significant heterogeneity (Tau² = 0.08; Chi² = 20.03, df = 11 (P = 0.04); I² = 45%).Secondary outcomesStatins had little or no effect on CrCl ( (15 studies, 3805 participants): MD 2.17 mL/min, 95% CI -0.32 to 4.66; I² = 31%) but lowered proteinuria ( (7 studies, 356 participants): MD -0.47 g/24 h, 95% CI -0.75 to -0.19) with marked heterogeneity (Tau² = 0.09; Chi² = 30.79, df = 6, P & 0.001), I² = 81%).Statins significantly lowered serum total cholesterol ( (25 studies, 2105 participants): MD -50.71 mg/dL, 95% CI -66.22 to -35.20; I² = 96%), LDL cholesterol ( (22 studies, 2054 participants): MD -43.58 mg/dL, 95% CI -53.56 to -33.60; I² = 92%), but had uncertain effects on HDL cholesterol ( (20 studies, 1245 participants): MD 2.59 mg/dL, 95% CI -0.59 to 5.76; I² = 83%). Statins significantly lowered triglycerides ( (18 studies, 1057 participants): MD -27.32 mg/dL, 95% CI -43.19 to -11.45; I² = 84%). Analyses for treatment effects on serum lipids showed evidence for marked heterogeneity (I² & 80% for all). Data for change in non-HDL cholesterol levels were not available, and thus, this outcome could not be evaluated.Sensitivity analysisWhen we limited analyses for major cardiovascular events, death, and MI to studies in which CVD was an exclusion criterion at baseline, we found similar treatment effects on major cardiovascular events (.1 (5 studies, 13,766 participants): RR 0.60, 95% CI 0.46 to 0.79; I² = 59%), death (.1 (3 studies, 7215 participants): RR 0.63, 95% CI 0.44 to 0.90; I² = 38%), and MI (.1 (4 studies, 7519 RR 0.54, 95% CI 0.38 to 0.76; I² = 0%) but had uncertain effects on cardiovascular mortality ( (1 study, 304 participants): RR 0.37, 95% CI 0.01 to 8.90). When we excluded
from the meta-analysis for major cardiovascular events, the summary treatment estimate was essentially unchanged (RR 0.70, 95% CI 0.63 to 0.78).Analysis of heterogeneityWe found significant heterogeneity in the meta-analyses for end-of-study total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, as well as for withdrawal from treatment, which we explored using prespecified subgroup analyses. Subgroup analyses to explore heterogeneity among studies for treatment effects on proteinuria were not possible due to an insufficient number of studies.For total cholesterol, dose of statin and baseline serum cholesterol were effect modifiers on the estimates we found, explaining 27.5% and 32.0% of heterogeneity, respectively. Higher doses of statin provided greater reductions in serum cholesterol than lower doses as expected (in simvastatin equivalent doses 40 to 80 mg/d, MD -94 mg/dL, 95% CI -143.9 to -44.1 mg/dL; 20 to 40 mg/d, MD -77 mg/dL, 95% CI -102.6 to -51.4 mg/dL; 0}