HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis

  • Review
  • Intervention

Authors

  • Suetonia C Palmer,

    1. University of Otago Christchurch, Department of Medicine, Christchurch, New Zealand
    Search for more papers by this author
  • Sankar D Navaneethan,

    1. Glickman Urological and Kidney Institute, Cleveland Clinic, Department of Nephrology and Hypertension, Cleveland, OH, USA
    Search for more papers by this author
  • Jonathan C Craig,

    1. The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia
    2. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
    Search for more papers by this author
  • David W Johnson,

    1. Princess Alexandra Hospital, Department of Nephrology, Woolloongabba, Queensland, Australia
    Search for more papers by this author
  • Vlado Perkovic,

    1. The George Institute for Global Health, Renal and Metabolic Division, Camperdown, NSW, Australia
    Search for more papers by this author
  • Jorgen Hegbrant,

    1. Diaverum Renal Services Group, Medical Office, Lund, Sweden
    Search for more papers by this author
  • Giovanni FM Strippoli

    Corresponding author
    1. The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia
    2. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
    3. University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy
    4. Mario Negri Sud Consortium, Department of Clinical Pharmacology and Epidemiology, Santa Maria Imbaro, Italy
    5. Diaverum, Medical-Scientific Office, Lund, Sweden
    6. Amedeo Avogadro University of Eastern Piedmont, Division of Nephrology and Transplantation, Department of Translational Medicine, Novara, Italy
    Search for more papers by this author

Abstract

Background

Cardiovascular 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) assessed previously; 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.

Objectives

To evaluate the benefits (such as reductions in all-cause and cardiovascular mortality, major cardiovascular events, MI and stroke; 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 methods

We 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 criteria

Randomised 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 analysis

Two 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 results

We 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 risk of bias overall; 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 participants; RR 0.72, 95% CI 0.66 to 0.79), all-cause mortality (10 studies, 28,276 participants; RR 0.79, 95% CI 0.69 to 0.91), cardiovascular death (7 studies, 19,059 participants; RR 0.77, 95% CI 0.69 to 0.87) and MI (8 studies, 9018 participants; RR 0.55, 95% CI 0.42 to 0.72). Statins had uncertain effects on stroke (5 studies, 8658 participants; 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 participants; 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 participants; RR 1.16, 95% CI 0.84 to 1.60), and cancer (2 studies, 5581 participants; 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' conclusions

Statins 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.

Résumé scientifique

Inhibiteurs de la réductase CoA HMG (statines) pour les individus atteints d'une maladie rénale chronique ne requérant pas de dialyse

Contexte

Les maladies cardiovasculaires (MCV) sont la première cause de décès chez les personnes aux premiers stades de l'insuffisance rénale chronique (IRC), pour lesquelles le risque absolu d'événements cardiovasculaires est semblable à celui des patients atteints de pathologies coronariennes existantes. Cette mise à jour d'une revue publiée en 2009 inclut des preuves issues de 27 nouvelles études (25 068 participants) en plus des 26 études (20 324 participants) évaluées précédemment et exclut trois études précédemment incluses (107 participants). Cette revue mise à jour comprend 50 études (45 285 participants), dont 38 (37 274 participants) ont fait l'objet d'une méta-analyse.

Objectifs

Évaluer les avantages (tels que des réductions dans la mortalité toutes causes ou cardiovasculaire, les événements cardiovasculaires majeurs, l'infarctus du myocarde et l'AVC ; et le ralentissement de la progression de l'IRC vers l'insuffisance rénale terminale (IRT)) et les inconvénients (dysfonctionnement musculaire et hépatique, arrêt du traitement et cancer) des statines par rapport au placebo, à l'absence de traitement, aux soins habituels ou à une autre statine chez les adultes atteints d'IRC qui ne sont pas sous dialyse.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur la néphrologie 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.

Critères de sélection

Nos recherches documentaires visaient les essais contrôlés randomisés (ECR) et les quasi-ECR comparant les effets des statines à un placebo, à l'absence de traitement, aux soins standard ou à d'autres statines, en termes de mortalité, d'événements cardiovasculaires, de fonction rénale, de toxicité et de taux de lipides chez les adultes atteints d'IRC non dialysés.

Recueil et analyse des données

Deux ou plusieurs auteurs ont indépendamment extrait les données et évalué les risques de biais des études. Les effets thérapeutiques ont été exprimés en différences moyennes (DM) pour les résultats continus (lipides, clairance de la créatinine et protéinurie) et en risques relatifs (RR) pour les résultats dichotomiques (événements cardiovasculaires majeurs, mortalité toutes causes, mortalité cardiovasculaire, infarctus du myocarde (IM) fatal ou non fatal, accident vasculaire cérébral (AVC) fatal ou non fatal, IRT, élévation des enzymes hépatiques, rhabdomyolyse, cancer et taux d'abandon) avec des intervalles de confiance (IC) à 95 %.

Résultats principaux

Nous avons inclus 50 études (45 285 participants) : 47 d'entre elles (39 820 participants) comparaient des statines à un placebo ou à l'absence de traitement et trois études (5 547 participants) comparaient deux schémas thérapeutiques différents pour l'administration de statines chez les adultes atteints d'IRC qui n'étaient pas encore sous dialyse. Nous avons pu effectuer une méta-analyse de 38 études (37 274 participants).

Le risque de biais dans les études incluses était élevé. Sept études comparant les statines à un placebo ou à l'absence de traitement avaient dans l'ensemble un risque de biais plus faible ; ces études étaient réalisées selon des protocoles publiés, leurs résultats étaient examinés par un comité, les résultats spécifiés y étaient rapportés et les analyses étaient effectuées en utilisant des méthodes en intention de traiter. Parmi les études contrôlées contre placebo ou l'absence de traitement, les événements indésirables ont été rapportés dans 32 études (68 %) et systématiquement évalués dans 16 études (34 %).

Comparativement au placebo, le traitement par statines a montré un effet cohérent dans la prévention des événements cardiovasculaires majeurs (13 études, 36 033 participants ; RR 0,72, IC à 95 % de 0,66 à 0,79), de la mortalité toutes causes confondues (10 études, 28 276 participants ; RR 0,79, IC à 95 % de 0,69 à 0,91), des décès d'origine cardiovasculaire (7 études, 19 059 participants ; RR 0,77, IC à 95 % de 0,69 à 0,87) et de l'IM (8 études, 9 018 participants; RR 0,55, IC 95% 0,42 à 0,72). Les statines avaient des effets incertains sur l'AVC (5 études, 8 658 participants ; RR 0,62, IC à 95 % de 0,35 à 1,12).

Les éventuels inconvénients du traitement par statines ont été limités par le manque de compte-rendus systématiques et étaient incertains dans les analyses avec de rares événements : élevation de la créatine kinase (7 études, 4 514 participants ; RR 0,84, IC à 95 % de 0,20 à 3,48), anomalies de la fonction hépatique (7 études, RR 0,76, IC à 95 % de 0,39 à 1,50), abandon en raison d'événements indésirables (13 études, 4 219 participants ; RR 1,16, IC à 95 % de 0,84 à 1,60) et cancer (2 études, 5 581 participants ; RR 1,03, IC à 95 % de 0,82 à 130).

Les statines avaient des effets incertains sur la progression de l'IRC. Les données concernant les effets relatifs de diminution importante du cholestérol chez les personnes aux premiers stades de l'insuffisance rénale étaient rares. Les statines réduisaient clairement les risques de décès, d'événements cardiovasculaires majeurs et d'IM chez les personnes atteintes d'IRC sans MCV à l'inclusion (prévention primaire).

Conclusions des auteurs

Les statines réduisaient de façon cohérente les décès et les événements cardiovasculaires majeurs de 20 % chez les personnes atteintes d'IRC non dialysées. Sur l'AVC et la fonction hépatique, les effets liés aux statines étaient imprécis et les effets indésirables du traitement sont encore mal compris. Les statines ont un rôle important dans la prévention primaire des événements cardiovasculaires et de la mortalité chez les personnes atteintes d'IRC.

Notes de traduction

Traduction réalisée par le Centre Cochrane Français

Resumo

Estatinas (inibidores da HMG-CoA redutase) para pessoas com doença renal crônica, sem necessidade de diálise

Introdução

A doença cardiovascular é a principal causa de morte das pessoas com doença renal crônica (DRC) em estágio inicial. Essas pessoas têm um risco absoluto de eventos cardiovasculares que é semelhante ao daquelas que têm doença coronariana preexistente. Esta é a atualização de uma revisão publicada originalmente em 2009 e inclui os resultados de 27 novos estudos (25.068 participantes), além dos 26 estudos já incluídos anteriormente (20.324 participantes); e exclui três estudos anteriormente incluídos (107 participantes). Esta atualização inclui, portanto, um total de 50 estudos (45.285 participantes), sendo que 38 estudos (37.274 participantes) foram incluídos em metanálises.

Objetivos

Avaliar os benefícios e efeitos adversos das estatinas comparadas com placebo, com ausência de tratamento, com o tratamento padrão ou com outras estatinas em adultos com doença renal crônica que não estejam em diálise. Os benefícios avaliados foram, por exemplo, redução de mortalidade cardiovascular por todas as causas, eventos cardiovasculares maiores, infarto do miocárdio e derrame e progressão lenta para doença renal crônica. Os efeitos adversos ou danosos foram disfunção muscular e hepática, retirada e câncer.

Métodos de busca

Fizemos buscas no Cochrane Renal Group’s Register até 5 de junho de 2012, usando termos relevantes para esta revisão.

Critério de seleção

Ensaios clínicos randomizados (ECR) e quasi-randomizados compararam os efeitos das estatinas versus placebo, nenhum tratamento, tratamento padrão ou outras estatinas, na mortalidade, nos eventos cardiovasculares, na função renal, na toxicidade e nos níveis dos lipídios em adultos com IRC sem diálise.

Coleta dos dados e análises

Dois ou mais revisores extraíram independentemente os dados e avaliaram o risco de viés dos estudos. Para os desfechos contínuos (lipídios, creatinina e proteinúria), apresentamos os resultados como diferença média (MD). Apresentamos como risco relativo (RR) com intervalos de confiança (IC) de 95% os resultados dos desfechos dicotômicos: eventos cardiovasculares, mortalidade geral, mortalidade cardiovascular, infarto do miocárdio (IM) fatal ou não fatal, acidente vascular cerebral fatal ou não fatal, IRC terminal aumento das enzimas hepáticas, rabdomiólise, câncer e taxa de abandono da medicação.

Principais resultados

Foram incluídos 50 estudos (45.285 participantes): 47 estudos (39.820 participantes) comparando as estatinas com placebo ou nenhum tratamento e três estudos (5.547 participantes) comparando dois regimes diferentes de estatinas em adultos com DRC sem diálise. Foi possível fazer metanálises com 38 estudos (37.274 participantes).

O risco de viés dos estudos incluídos foi alto. Sete estudos comparando as estatinas com placebo ou nenhum tratamento tiveram menor risco de viés global. Esses estudos foram conduzidos de acordo com os protocolos publicados, os desfechos foram julgados por um comitê, os desfechos especificados foram relatados e as análises foram realizadas conforme “intenção 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 comparação com placebo, o uso das estatinas preveniu a ocorrência de eventos cardiovasculares (13 estudos, 36.033 participantes; RR 0,72, IC 95% 0,66 a 0,79), a mortalidade global (10 estudos, 28.276 participantes; RR 0,79, IC 95% 0,69 a 0,91), mortalidade de causa cardiovascular (7 estudos, 19.059 participantes; RR 0,77, IC 95% 0,69 a 0,87) e infarto (8 estudos, 9.018 participantes; RR 0,55, IC 95% 0,42 a 0,72). O efeito das estatinas sobre a taxa de acidente vascular cerebral não foi significativo (5 estudos, 8.658 participantes; RR 0,62, IC 95% 0,35 a 1,12).

A falta de descrição sistemática dos eventos adversos relacionados ao uso das estatinas limitou nossa avaliação desse desfecho. Nos estudos que relataram esse desfecho, os eventos adversos foram raros e isso prejudicou sua avaliação: aumento da creatinino-quinase (CPK) (7 estudos, 4.514 participantes; RR 0,84, IC 95% 0,20 a 3,48), alteração da função hepática (7 estudos, RR 0,76, IC 95% 0,39 a 1,50), abandono do tratamento devido a eventos adversos (13 estudos, 4.219 participantes; RR 1,16, IC 95% 0,84 a 1,60) e câncer (2 estudos, 5.581 participantes; RR 1,03, IC 95% 0,82 a 130).

O efeito das estatinas sobre a progressão da DRC foi inconsistente. Houve poucos dados sobre os efeitos relativos da redução intensiva de colesterol em pessoas em estágios iniciais da doença renal. O uso das estatinas produziu uma redução consistente do risco de mortalidade, eventos cardiovasculares maiores e infarto em pessoas com DRC sem doença cardiovascular preexistente (prevenção primária).

Conclusão dos autores

Em pessoas com DRC que não precisam de diálise, 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 função renal foram inconsistentes. Os efeitos adversos do tratamento com estatinas para esse tipo de paciente ainda não estão claros. As estatinas têm um papel importante na prevenção primária de eventos cardiovasculares e na taxa de mortalidade em pessoas com DRC.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva). Contato: tradutores@centrocochranedobrasil.org.br

Plain language summary

Statins can help reduce risk of death in people with chronic kidney disease who do not need dialysis

Adults 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.

Résumé simplifié

Les statines peuvent aider à réduire le risque de décès chez les personnes atteintes d'insuffisance rénale chronique qui ne nécessitent pas de dialyse

Les adultes atteints d'insuffisance rénale chronique (IRC) ont un risque élevé de développer des complications de maladie cardiaque.On pense que le traitement par statines diminue le cholestérol et réduit les risques de décès et de complications de maladie cardiaque.

Nous avons examiné 50 études publiées 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 constaté que les statines réduisaient les risques de décès et d'événements cardiaques majeurs de 20 %. Le traitement par statines s'est également avéré efficace dans la réduction des maladies et des décès cardiaques chez les personnes atteintes d'IRC sans maladie cardiaque. Chez ces personnes, le traitement par statines réduit les risques de crise cardiaque de moitié.

Les statines ont de potentiels effets nocifs sur la fonction hépatique et musculaire ainsi que sur certains cancers. Nous avons constaté que ces questions n'étaient pas bien analysées dans les études que nous avons évaluées, et ces effets ne sont pas bien compris.

Bien que l'utilisation des statines n'ait pas réduit clairement les risques de progression de l'insuffisance rénale, elles peuvent être recommandées pour réduire les risques de décès et d'événements cardiaques chez les personnes qui sont aux premiers stades de l'insuffisance rénale. Cependant, les effets secondaires potentiels sont incertains et doivent être davantage étudiés.

Notes de traduction

Traduction réalisée par le Centre Cochrane Français

Resumo para leigos

Estatinas podem ajudar a reduzir o risco de morte em pessoas com doença renal crônica que não precisam de diálise

Adultos com doença renal crônica (DRC) têm alto risco de desenvolver complicações decorrentes de doenças do coração (doenças cardíacas). Acredita-se que o tratamento dessas pessoas com estatinas reduz o seu colesterol e o risco de elas morrerem e de terem complicações cardíacas.

Avaliamos 50 estudos publicados antes de junho de 2012 a respeito do uso de estatinas em mais de 45.000 pessoas com DRC que não precisavam de diálise. Concluímos que as estatinas reduziram em 20% o risco de morte e de problemas cardíacos graves nessas pessoas. O tratamento com estatina também mostrou ser eficaz na redução de doença cardíaca e na diminuição da mortalidade de pessoas com DRC que não têm doença cardíaca. Nessas pessoas, o tratamento com estatina reduziu os riscos de ataque cardíaco pela metade.

As estatinas podem causar alguns efeitos adversos os músculos, no funcionamento do fígado e propiciar o surgimento de alguns tipos de câncer. Descobrimos que essas questões não foram bem analisadas nos estudos incluídos nesta revisão e, portanto, esses efeitos ainda não estão claros.

Embora as estatinas não reduzam a progressão da doença renal, elas são recomendadas para reduzir os riscos de morte e eventos cardíacos nas pessoas com doença renal em estágio inicial. No entanto, os possíveis efeitos colaterais desse remédio ainda são incertos e precisam ser melhor estudados.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva). Contato: tradutores@centrocochranedobrasil.org.br

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. Absolute approximate events rates of outcomes per year were derived from previous observational cohort studies. Absolute numbers of people on dialysis with cardiovascular or mortality events avoided or incurred per 1000 treated were estimated using these assumed risks together with the estimated relative risks and 95% confidence intervals. (Anavekar 2004; Di Angelantonio 2010; Weiner 2006)

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 treated
Placebo 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: Confidence interval; RR: Risk Ratio
GRADE 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 estimate

Background

Description of the condition

The global incidence and prevalence of chronic kidney disease (CKD) is increasing (Couser 2011; Grassmann 2005). 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 (Coresh 2007). 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 (USRDS 2011). Similarly, a large proportion of people with earlier stages of kidney disease die of cardiovascular disease before they develop end-stage kidney disease (ESKD) (Foley 2005). People with CKD not on dialysis have risks of death or complications from cardiovascular disease that are equivalent to people with existing heart disease (Go 2004; Henry 2002).

How the intervention might work

Many traditional and non-traditional cardiovascular risk factors are prevalent in people with CKD (Muntner 2005; Shilpak 2005). Elevated serum cholesterol and triglycerides are present in 60% of people with CKD and an even higher proportion of people who have nephrotic syndrome (Harris 2002). Abnormal lipid levels may contribute to the development of cardiovascular disease (CVD) and initiation and progression of CKD (Drueke 2001; Schaeffner 2003). In the Atherosclerosis Risk in Communities Study (ARIC) and Physicians Health study, elevated lipid levels were associated with lower kidney function (Manjunath 2003). 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 (Kasiske 1988). Statins could reduce kidney disease progression and incidence of CVD in people with kidney dysfunction (Massy 2001).

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% (Baigent 2005).

Why it is important to do this review

In 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 (Navaneethan 2009).

New data from SHARP Study 2010 and post hoc analyses in subgroups of people with CKD in larger studies have become available since our last review was published in 2009 (4S 1993; AFCAPS/TexCAPS 1997; ASCOT-LLA 2003; CARDS 2003; JUPITER Study 2007). In 2011, an advisory committee that considered data from the Study of Heart and Renal Protection study (SHARP Study 2010) voted to recommend the use of simvastatin or ezetimibe or both for people with CKD not on dialysis (FDA 2011).

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.

Objectives

To evaluate the benefits (such as reductions in all-cause and cardiovascular mortality, major cardiovascular events, MI and stroke; 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.

Methods

Criteria for considering studies for this review

Types of studies

RCTs 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 (Briel 2006).

Types of participants

Inclusion criteria

Studies enrolling adults with CKD (defined and staged according to Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines) (Levey 2003) 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 criteria

Studies 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 (Palmer 2013; Palmer 2014).

Types of interventions

We 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 measures

Primary outcomes
  1. Major cardiovascular events

  2. All-cause mortality

  3. Cardiovascular mortality

  4. Fatal and non-fatal MI

  5. Fatal and non-fatal stroke

  6. ESKD

  7. Adverse events attributable to intervention

    1. Elevated creatine kinase

    2. Elevated liver enzymes

    3. Withdrawal due to adverse events

    4. Cancer.

Secondary outcomes
  1. End of treatment creatinine clearance (CrCl) or glomerular filtration rate (GFR) (any measure)

  2. End of treatment proteinuria (micro or macroalbuminuria)

  3. Serum lipid levels

    1. Total cholesterol

    2. Low density lipoprotein (LDL) cholesterol

    3. High density lipoprotein (HDL) cholesterol

    4. Triglycerides.

Search methods for identification of studies

Electronic searches

We 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.

  1. Quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of renal-related journals and the proceedings of major renal conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected renal journals

  6. Searches 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 Cochrane Renal Group.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of clinical practice guidelines, review articles and relevant studies.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

2009 review

The 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 studies

For 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 were not applicable; 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 management

Data 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 studies

The following items were independently assessed by two authors using the risk of bias assessment tool (Higgins 2011) (Appendix 2).

  • 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 personnel

    • Outcome 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 effect

For 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 data

Any 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 (Higgins 2011).

Assessment of heterogeneity

Heterogeneity 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 (Higgins 2003). I² values of 25%, 50% and 75% correspond to low, medium and high levels of heterogeneity.

Assessment of reporting biases

To 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 (Harbord 2006). We conducted analyses using Comprehensive Meta-Analysis (Version 2, Biostat, Englewood, NJ, 2005).

Data synthesis

We 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 (Guyatt 2008). 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 (Anavekar 2004; Di Angelantonio 2010; Weiner 2006).

Subgroup analysis and investigation of heterogeneity

We 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 analysis

We performed sensitivity analyses to explore the influence of the following factors on effect size.

  • Repeating the analysis excluding unpublished studies

  • Repeating the analysis taking account of risk of bias

  • Repeating the analysis excluding any very long or large studies to establish how much they dominate the results

  • Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), country.

Results

Description of studies

2009 review

We included 26 studies (25,017 participants) (Bianchi 2003; Buemi 2000; Dalla Nora 2003; Fried 2001; Gheith 2002; Hommel 1992; HPS 2002; Imai 1999; Lam 1995; Lee 2002; LIPS Study 2005; Nakamura 2002; Nielsen 1993; PPP Study 1992; PREVEND IT 2000; Rayner 1996; Scanferla 1991; Stegmayr 2005; Thomas 1993; Tonolo 1997; UK-HARP-I 2005; Van Dijk 2001; Verma 2005; Yasuda 2004; Zhang 1995) in this review for data available at July 2008 (Navaneethan 2009).

Results of the search

2014 review update

We removed three studies (107 participants) from our 2009 review because adults with CKD were not included (Dalla Nora 2003); data were available in another publication (duplicate publication of Lee 2002) or the study duration was less than eight weeks duration (Van Dijk 2001). We noted that in the 2009 review, all diabetic participants in the HPS 2002 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 (Figure 1). 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 included only children; 441 did not evaluate statins; 17 were ongoing studies not relevant to this review; 11 were fewer than eight weeks duration; 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 conducted in children; 12 studies did not compare statin treatment with placebo, no treatment or another statin; and eight studies were of short duration (< eight weeks).

Figure 1.

Study flow diagram.

*Other - short duration, animal studies

We included 27 new studies (25,068 participants), 24 studies (19,521 participants) comparing statin with placebo or no treatment (4S 1993; AFCAPS/TexCAPS 1997; ALLIANCE Study 2000; Aranda 1994; ASCOT-LLA 2003; CARDS 2003; Di Lullo 2005; Dummer 2008; ESPLANADE Study 2010; Fassett 2010; Goicoechea 2006; JUPITER Study 2007; Lintott 1995; LORD Study 2006; MEGA Study 2004; Mori 1992; Nakamura 2005; Nakamura 2006; Panichi 2005; Renke 2010a; Samuelsson 2002; Sawara 2008; SHARP Study 2010; Tokunaga 2008) and three studies (5547 participants) compared two statin regimens (IDEAL Study 2004; PANDA Study 2011; TNT Study 2005).

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 studies; 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 (4S 1993; AFCAPS/TexCAPS 1997; ALLIANCE Study 2000; ASCOT-LLA 2003; CARDS 2003; HPS 2002; JUPITER Study 2007; LIPS Study 2005; MEGA Study 2004; PPP Study 1992). Two comparisons provided post hoc data for 5428 adults comparing two statin regimens (IDEAL Study 2004; TNT Study 2005).

We included 38 studies that involved 37,274 adult participants that compared statins with placebo or no treatment in our meta-analyses.

Included studies

Statin versus placebo or no treatment

Studies varied in sample size (median 56 participants; range 14 to 1233 participants). There were eight comparisons that included more than 1000 participants (4S 1993; ASCOT-LLA 2003; HPS 2002; JUPITER Study 2007; MEGA Study 2004; PPP Study 1992; SHARP Study 2010).

The median statin dose (equivalent to simvastatin) was 20 mg (range 5 to 80 mg/d). Statin interventions included atorvastatin (ALLIANCE Study 2000; ASCOT-LLA 2003; Bianchi 2003; CARDS 2003; Goicoechea 2006; LORD Study 2006; Renke 2010a; Stegmayr 2005), cerivastatin (Nakamura 2002), fluvastatin (Buemi 2000; Di Lullo 2005; ESPLANADE Study 2010; Gheith 2002; Lintott 1995; LIPS Study 2005; Samuelsson 2002; Yasuda 2004), lovastatin (AFCAPS/TexCAPS 1997; Lam 1995), pitavastatin (Nakamura 2005; Nakamura 2006; Tokunaga 2008), pravastatin (Aranda 1994; Fassett 2010; Imai 1999; Lee 2002; MEGA Study 2004; Mori 1992; PPP Study 1992; PREVEND IT 2000; Zhang 1995), rosuvastatin (JUPITER Study 2007; Sawara 2008; Verma 2005), simvastatin (4S 1993; Dummer 2008; Fried 2001; Hommel 1992; HPS 2002; Nielsen 1993; Panichi 2005; Rayner 1996; Thomas 1993; Tonolo 1997; UK-HARP-I 2005), simvastatin and ezetimibe (SHARP Study 2010), and simvastatin or pravastatin (Scanferla 1991).

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 (4S 1993; ALLIANCE Study 2000; LIPS Study 2005), 10 studies excluded participants with clinical coronary artery disease (AFCAPS/TexCAPS 1997; CARDS 2003; Fried 2001; Imai 1999; JUPITER Study 2007; Lam 1995; MEGA Study 2004; Nakamura 2002; Nakamura 2005; SHARP Study 2010). Median baseline low density lipoprotein cholesterol was 225 mg/dL (range 136 to 390 mg/dL).

Eight studies included only participants who had diabetes (CARDS 2003; Hommel 1992; Lam 1995; Mori 1992; Nakamura 2005; Nielsen 1993; Tonolo 1997; Zhang 1995); and people with diabetes were excluded from seven studies (Bianchi 2003; Gheith 2002; Lee 2002; Nakamura 2002; Nakamura 2006; Panichi 2005; Renke 2010a).

Stegmayr 2005 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 SHARP Study 2010 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 (Sacks 1996; LIPID 1998; Shepherd 1995) conducted in the general population, and were included as a single comparison (PPP Study 1992).

Statin versus other statin

PANDA Study 2011 and TNT Study 2005 compared two doses of atorvastatin and IDEAL Study 2004 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 studies

See: Characteristics of excluded studies

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 (ALLHAT & ALHAT-LLT 1996; ATIC Study 2005; David 2008; Deighan 2001; Kano 2003; MASTERPLAN Study 2005; Nakamura 2010a; Samuelsson 1997; STENO-2 Study 1999; Tokunaga 2004; Tonolo 2006; UK-HARP-II 2006; Yasuda 2010); did not assess treatment effects in patients with CKD not requiring dialysis (AURORA Study 2005; Dalla Nora 2003; Kostapanos 2007; Paniagua 2002); were not RCTs (Dyadyk 2006; Nakamura 2001c; Rammos 2005; Yigit 2004); included children (Garcia-de-la-Puente 2009; Kano 2003; Mackie 2010); or provided follow-up of an unclear duration or were fewer than eight weeks (Dogra 2005; Dogra 2007; Golper 1987; Golper 1989; Ott 2008; Paulsen 2010; Schmieder 2003; Torraca 2006; Van Dijk 2001).

Risk of bias in included studies

The risk of bias in the included studies was high (Figure 2; Figure 3). Seven studies comparing statins with placebo or no treatment had lower risk of bias overall; 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 (4S 1993; HPS 2002; JUPITER Study 2007; PPP Study 1992; PREVEND IT 2000; SHARP Study 2010; UK-HARP-I 2005). 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 studies

Figure 3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study

In 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.

Allocation

Random sequence generation was low risk in fewer than 25% of included studies, and allocation concealment was low risk in only 30%.

Blinding

Participants and personnel were blinded in 40% of studies, and outcome assessors were blinded in only 25%.

Incomplete outcome data

Completeness of outcome reporting and intention-to-treat analysis methodology was applied in 25% of included studies.

Selective reporting

We 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 (Duval 2000) 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 bias

The risk of bias due to sources of funding was high in 20%, low in 32% and unclear in 48% of studies.

Effects of interventions

See: Summary of findings for the main comparison

Primary outcomes

We found moderate-to-high quality evidence that statin therapy reduced major cardiovascular events (Analysis 1.1 (13 studies, 36,033 participants): RR 0.72, 95% CI 0.66 to 0.79; I² = 40%), all-cause mortality (Analysis 1.2 (10 studies, 28,726 participants): RR 0.79, 95% CI 0.69 to 0.91; I² = 32%), and cardiovascular mortality (Analysis 1.3 (7 studies, 19,059 participants): RR 0.77, 95% CI 0.69 to 0.87; I² = 0% ) (Summary of findings for the main comparison).

Statins markedly lowered risk of fatal or non-fatal MI (Analysis 1.4 (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 (Analysis 1.5 (5 studies, 8658 participants): RR 0.63, 95% CI 0.35 to 1.12; I² = 53%). There was no significant heterogeneity in these analyses.

SHARP Study 2010 reported statins had little or no effect on progression to ESKD (Analysis 1.6 (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 (Analysis 1.7 (7 studies, 4514 participants): RR 0.84, 95% CI 0.20 to 3.48; I² = 0%), liver dysfunction (Analysis 1.8 (7 studies, 7991 participants): RR 0.76, 95% CI 0.39 to 1.50; I² = 0%), withdrawal due to adverse events (Analysis 1.9 (13 studies, 4219 participants): RR 1.16, 95% CI 0.84 to 1.60; I² = 45%), and cancer (Analysis 1.10 (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 outcomes

Statins had little or no effect on CrCl (Analysis 1.11 (15 studies, 3805 participants): MD 2.17 mL/min, 95% CI -0.32 to 4.66; I² = 31%) but lowered proteinuria (Analysis 1.12 (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 (Analysis 1.13 (25 studies, 2105 participants): MD -50.71 mg/dL, 95% CI -66.22 to -35.20; I² = 96%), LDL cholesterol (Analysis 1.14 (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 (Analysis 1.15 (20 studies, 1245 participants): MD 2.59 mg/dL, 95% CI -0.59 to 5.76; I² = 83%). Statins significantly lowered triglycerides (Analysis 1.16 (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 analysis

When 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 (Analysis 1.17.1 (5 studies, 13,766 participants): RR 0.60, 95% CI 0.46 to 0.79; I² = 59%), death (Analysis 1.18.1 (3 studies, 7215 participants): RR 0.63, 95% CI 0.44 to 0.90; I² = 38%), and MI (Analysis 1.19.1 (4 studies, 7519 participants; RR 0.54, 95% CI 0.38 to 0.76; I² = 0%) but had uncertain effects on cardiovascular mortality (Analysis 1.20 (1 study, 304 participants): RR 0.37, 95% CI 0.01 to 8.90). When we excluded SHARP Study 2010 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 heterogeneity

We 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 to 20 mg/d MD -42.5 mg/dL, 95% CI -55.1 to -30.0 mg/dL). A higher total cholesterol at baseline resulted in greater reductions in serum cholesterol with treatment (baseline serum cholesterol > 230 mg/dL, MD -70.2 95% CI -86.9 to -53.5 mg/dL versus < 230 mg/dL, MD -35.4 mg/dL, 95% CI -50.3 to -20.6 mg/dL).

Only baseline serum cholesterol modified treatment effects on LDL cholesterol, which explained 48.7% of the heterogeneity observed in this meta-analysis. A higher total cholesterol at baseline resulted in greater reductions in LDL cholesterol with treatment (baseline serum cholesterol > 230 mg/dL, MD -58.6 95% CI -68.4 to -48.9 mg/dL versus < 230 mg/dL, MD -30.9 mg/dL 95% CI -40.2 to -21.6 mg/dL).

Subgroup analyses did not explain the heterogeneity observed in outcomes for HDL cholesterol or triglycerides.

Subgroup analysis indicated that baseline kidney function (98.8% of heterogeneity explained), proportion with diabetes (99.6%), and adequacy of allocation concealment (100%) modified the observed risks of treatment withdrawal. A lower GFR (< 60 mL/min/1.73 m²) was associated with a higher risk of withdrawal (RR 1.57, 95% CI 1.16 to 2.12) compared with GFR > 60 mL/min/1.73 m² (RR 1.02, 95% CI 0.77 to 1.37); a higher proportion of people with diabetes was associated with higher risk of withdrawal (> 50%: RR 1.89, 95% CI 0.34 to 10.5); (20% to 50%: RR 1.51, 95% CI 1.12 to 2.05); (< 20% RR 0.85, 95% CI 0.70 to 1.03); adequate allocation concealment was associated with a lower risk of withdrawal (adequate: RR 0.85, 95% CI 0.71 to 1.03 versus inadequate or unclear allocation concealment: RR 1.56, 95% CI 1.17 to 2.07).

The available data did not enable exploration of between-statin differences in effectiveness.

Discussion

Summary of main results

This review update confirmed findings from our 2009 review (Navaneethan 2009). We found moderate-to-high quality data to indicate that statins consistently reduced risk of death and major cardiovascular events by 20% to 25% in people with CKD not on dialysis. Although statin therapy also reduced risk of MI by nearly half, effects on the rate of stroke remain uncertain. Statins clearly reduce risks of death, major cardiovascular events and MI in people who do not have CVD (primary prevention).

Taking into account estimated baseline risk without treatment (Summary of findings for the main comparison), statin therapy of 1000 people with CKD for one year might be expected to prevent six major cardiovascular events and five deaths from any cause, and five years of treating 1000 people may prevent 30 major cardiovascular events and 25 deaths.

The adverse effects of statins in people with CKD are uncertain; adverse events were systematically characterised by about a third of the included studies, and treatment effects were uncertain. Withdrawal from treatment may occur more frequently among those with lower kidney function or pre-existing diabetes, suggesting that these people may be more at risk of treatment-related toxicity.

Statins lower serum cholesterol significantly in analyses limited by marked heterogeneity, explained in part by the statin dose used and serum cholesterol levels at treatment commencement. Statins lower proteinuria, but have uncertain effects on kidney function or risk of progression to ESKD.

Data comparing different statins or different doses of statins were sparse in adults with CKD.

Overall completeness and applicability of evidence

Current data of the effects of statins in people with earlier stages of kidney disease relating to mortality were primarily derived from posthoc subgroup analyses from major studies in larger populations (4S 1993; ALLIANCE Study 2000; CARDS 2003; JUPITER Study 2007; MEGA Study 2004; PPP Study 1992; PREVEND IT 2000). Data for treatment effects on cardiovascular events were also predominantly derived from posthoc subgroup analyses (4S 1993; AFCAPS/TexCAPS 1997; ALLIANCE Study 2000; CARDS 2003; HPS 2002; JUPITER Study 2007; LIPS Study 2005; MEGA Study 2004; PPP Study 1992; PREVEND IT 2000), as well as the recently published SHARP Study 2010. Although data for treatment effects in people with CKD that were derived from posthoc analyses in larger studies may be less reliable (Boutron 2010), we found no heterogeneity in the analyses for cardiovascular events and mortality, suggesting that effects estimates in all studies were similar regardless of whether analyses based on CKD were prespecified or posthoc.

Outcome data for statins were scant in several important settings. SHARP Study 2010 assessed ezetimibe (a drug that lowers cholesterol absorption in the intestine) combined with simvastatin. There were insufficient data to determine if treatment effects differed between combination therapy and treatment with a statin alone. Furthermore, it was unclear if treatment benefits for statins depended on treatment-related reductions in serum cholesterol: there were insufficient numbers of studies that reported both cardiovascular and mortality outcomes and changes in cholesterol levels with treatment.

Based on current evidence, no conclusions could be made about whether statin therapy can slow CKD progression. Currently, evidence for progression to ESKD relies on data from SHARP Study 2010 alone, and treatment effects of statins on this outcome remain uncertain despite reporting more than 2000 events. Based on evidence from SHARP Study 2010, statins probably do not have a clinically important benefit on kidney function.

Potential biases in the review process

Although review strengths included conduct by independent authors, a comprehensive literature search designed by a specialist librarian to include grey literature and examination of all potentially relevant outcomes, potential biases exist in the review process.

We were unable to include data for people with CKD not on dialysis from the SHARP Study 2010 or Stegmayr 2005 studies for all-cause mortality and cardiovascular mortality. Reported data for these outcomes combined results for people on dialysis with those at earlier stages of kidney disease not on dialysis; separate unpublished data for earlier stages of kidney disease were not available.

Nearly two-thirds of the included studies did not systematically evaluate and report adverse events associated with statins. Consequently, the relative harms of statins remain uncertain and incompletely studied (high risk of bias).

Data for treatment effects on stroke suggested a potential for benefit, but were limited by few events and wider confidence intervals.

Furthermore, heterogeneity (inconsistency in treatment effects observed between studies beyond the level of chance) was present in analyses for serum lipids and proteinuria that were incompletely explained by subgroup analyses.

Agreements and disagreements with other studies or reviews

This update confirmed our earlier review findings that statins reduce serious cardiovascular events and mortality in people with CKD not requiring dialysis (New Reference). The finding that statins proportionally reduce cardiovascular death by 20% is similar to our previous prospective meta-analysis in broader populations of people who had, or were at risk for, CVD which showed that statins lowered lipids to reduce coronary-related mortality at a rate of 20% (Baigent 2005). Given that people with CKD have a risk of cardiovascular events equivalent to people with existing coronary artery disease (Foley 1998), the absolute benefits of statins in people with CKD are similar to other populations with CVD, or adults who have 20% or more 10-year risk of developing CVD, for whom statins are recommended (NICE 2006).

We also found that statins reduced all-cause mortality by approximately 20%, similar to the 10% proportional reduction in broader populations (Baigent 2005). Inclusion of additional studies conducted in populations with CKD without clinically evident CVD in this review (AFCAPS/TexCAPS 1997; CARDS 2003; JUPITER Study 2007; MEGA Study 2004; SHARP Study 2010) indicated that statins have a role in the primary prevention of death and major cardiovascular events in people who have CKD.

Intense lipid lowering is associated with additional cardiovascular benefits in the general population (CTT Collaboration 2010). Similar data for intensive lipid lowering in people with CKD however depend on posthoc analyses in two studies (PANDA Study 2011; TNT Study 2005). This needs further investigation, including systematic analysis of treatment-related toxicity. Statins do not prevent progression of kidney disease.

Notably, the finding that statins significantly reduce adverse cardiovascular outcomes in people with earlier stages of CKD contrasts with a similar systematic review and meta-analysis we have conducted of studies in people with advanced kidney disease on dialysis (Palmer 2013). Statin therapy in people with advanced CKD on dialysis has little of no effect on major cardiovascular events (RR 0.95, 95% CI 0.88 to 1.03), all-cause mortality (RR 0.96, 95% CI 0.90 to 1.02), cardiovascular mortality (RR 0.94, 95% CI 0.84 to 1.06), or MI (RR 0.87, 95% CI 0.71 to 1.07) with uncertain effects on liver or muscle function or cancer, despite similar reduction in cholesterol levels. In a separate analysis (data not shown), we showed that differences in treatment effects based on severity of kidney disease were statistically different, and people with earlier stages of kidney disease gain greater benefits from lipid lowering compared with people on dialysis who receive little or no benefit from statin treatment.

The beneficial effect of statins on cardiovascular end-points observed in our review may be potentially explained by either cholesterol-dependent or cholesterol-independent effects or both. In addition to the well-documented association between cholesterol lowering and cardiovascular risk reduction in non-CKD populations (Baigent 2005), statins may modulate cardiovascular risk by decreasing inflammation, enhancing endothelial function, inhibiting smooth muscle proliferation, exerting direct anti-thrombotic properties and stabilising pre-existing atherosclerotic plaque (Kinlay 2003; Robinson 2005; Sotiriou 2000). Similar mechanisms may underpin the beneficial actions of statins on progression of kidney disease, although other cholesterol-independent renoprotective actions such as inhibition of renal cell proliferation, anti-fibrotic effects, suppression of macrophage recruitment, anti-oxidation, and down-regulation of inflammatory cytokines, may also contribute (Campese 2005; Keane 2000).

The NKF-DOQI guidelines recommend initiating low dose statin treatment in people with CKD stages 3 to 5 (eGFR)15 to 60 mL/min/1.73 m² when LDL cholesterol is above 130 mg/dL in addition to therapeutic lifestyle changes (Table 1; KDOQI 2003). The Caring for Australasians with Renal Impairment (CARI) guideline suggests initiating statin therapy if the LDL level is above 100 mg/dL (Walker 2005, currently under revision). A guideline on the treatment of lipids in CKD by the Kidney Disease improving Global Outcomes is in development (KDIGO 2013).

Table 1. Published guidelines on management of hyperlipidaemia in chronic kidney disease
  1. CKD - chronic kidney disease; TC - total cholesterol; Non-HDL - Non high-density lipoprotein cholesterol; TG - triglyceride levels; LDL - low-density lipoprotein cholesterol; TLC - therapeutic lifestyle changes
    ¹ Stage 3: GFR 30 to 59 mL/min; stage 4: GFR 15 to 29 mL/min; stage 5: GFR < 15 mL/min
    ² If LDL > 100 after 3 months of TLC initiation, statin therapy should be initiated
    ³ If LDL > 100 after 6 weeks of low dose statins, dose should be increased
    ⁴ Stage of CKD not mentioned

GuidelinesCountryYearStage of CKDLipids (mg/dL)Treatment
National Kidney Foundation-Kidney Disease Outcomes Quality initiative (NKF-DOQI) KDOQI 2003USA2003Stages 3, 4, 5¹
  1. LDL 100 to 129

  2. LDL > 130

  3. TG > 200 and non-HDL > 130

  1. TLC²

  2. TLC + low dose statin³

  3. TLC + low dose statin

Caring for Australians with renal impairment (CARI) Walker 2005Australia2005CKD⁴

TC > 166

LDL > 100

TG > 200

Initiate statin therapy if LDL > 100 mg/dL

Guideline currently being updated

Canadian Society of Nephrology (CSN)Canada2005--No guideline availableNo guideline available
Kidney Disease Improving Global Outcomes (KDIGO)Global2012--Anticipated guideline in 2012Anticipated guideline in 2012

Our analysis confirms the benefits anticipated by statin therapy in people with early stages of CKD (including primary prevention of death and cardiovascular events) and supports the present guidelines. Clear recommendations about target serum cholesterol levels in future guidelines cannot be made based on the present data and would benefit from an individual patient data meta-analysis for clarification.

Authors' conclusions

Implications for practice

Moderate-to-high quality evidence currently supports the widespread use of statins for people with CKD not on dialysis to prevent death and cardiovascular events, including people without existing CVD. Statins significantly reduce death and major cardiovascular events, including MI in this population, although effects on the risk of stroke were less certain. Treating 1000 people with CKD not on dialysis may prevent 30 major cardiovascular events and 25 deaths over five years.

Statins have uncertain effects on progression of kidney disease and cannot be recommended to slow progression of CKD. Currently, toxicity of statins for people with CKD are poorly characterised, and this needs to be acknowledged when commencing treatment. It remains unclear whether people with kidney disease who commence dialysis should have statins discontinued, but treatment benefits are likely to be small or absent.

Implications for research

Available data confirms the benefit of statins in reducing lipid levels and improving all-cause and cardiovascular mortality in people with earlier stages of CKD. Future research, including post-marketing surveillance, is particularly required to monitor the safety of statins in people with CKD, with a focus on risks of muscle or liver damage associated with longer-term treatment. A coordinated approach to post-marketing surveillance might be considered.

Currently, the available evidence depends largely on posthoc analyses from larger studies; future prospective studies of primary prevention in people with moderate to severe CKD (eGFR 15 to 60 mL/min/1.73 m²), including detailed assessment of treatment toxicity, are warranted.

Specific studies of primary and secondary prevention of cardiovascular events in people with CKD not on dialysis would be informative for clinical practice.

Acknowledgements

We acknowledge the contributions of study authors (Drs Baigent, Tonnelli, Stegmayr, Lins, Thomas, Zhang, Van Dijk, Kosch and Nakamura) who provided data about their studies upon request. We would like to thank the referees for their editorial advice during the preparation of this review. We also thank the Cochrane Renal Group's Narelle Willis, for her help in coordinating and editing this review, and Ruth Mitchell and Gail Higgins for assistance in the development of search strategies.

We also wish to thank Francesca Pansini, Carlo Manno and Fabio Pellegrini who contributed to the design, quality assessment, data collection, entry, analysis and interpretation and writing of the first version of this review (Navaneethan 2009).

Data and analyses

Download statistical data

Comparison 1. Statins versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Major cardiovascular events1336033Risk Ratio (IV, Random, 95% CI)0.72 [0.66, 0.79]
2 All-cause mortality1028276Risk Ratio (IV, Random, 95% CI)0.79 [0.69, 0.91]
3 Cardiovascular mortality719059Risk Ratio (IV, Random, 95% CI)0.77 [0.69, 0.87]
4 Fatal and non-fatal myocardial infarction89018Risk Ratio (IV, Random, 95% CI)0.55 [0.42, 0.72]
5 Fatal and non-fatal stroke58658Risk Ratio (IV, Random, 95% CI)0.63 [0.35, 1.12]
6 End-stage kidney disease1 Risk Ratio (IV, Random, 95% CI)Totals not selected
7 Elevated creatine kinase (rhabdomyolysis)74514Risk Ratio (IV, Random, 95% CI)0.84 [0.20, 3.48]
8 Elevated liver enzymes77991Risk Ratio (IV, Random, 95% CI)0.76 [0.39, 1.50]
9 Withdrawal due to adverse events134219Risk Ratio (IV, Random, 95% CI)1.16 [0.84, 1.60]
10 Cancer25581Risk Ratio (IV, Random, 95% CI)1.03 [0.82, 1.30]
11 End of treatment creatinine clearance (CrCl)153805Mean Difference (IV, Random, 95% CI)2.17 [-0.32, 4.66]
11.1 CrCl [mL/min]7319Mean Difference (IV, Random, 95% CI)5.19 [0.58, 9.79]
11.2 CrCl [mL/min/1.73 m²]83486Mean Difference (IV, Random, 95% CI)0.97 [0.40, 1.54]
12 End of treatment proteinuria7356Mean Difference (IV, Random, 95% CI)-0.47 [-0.75, -0.19]
13 Total cholesterol252105Mean Difference (IV, Random, 95% CI)-50.71 [-66.22, -35.20]
14 LDL cholesterol222054Mean Difference (IV, Random, 95% CI)-43.58 [-53.56, -33.60]
15 HDL cholesterol201245Mean Difference (IV, Random, 95% CI)2.59 [-0.59, 5.76]
16 Triglycerides181057Mean Difference (IV, Random, 95% CI)-27.32 [-43.19, -11.45]
17 Sensitivity analysis: major cardiovascular events1336033Risk Ratio (IV, Random, 95% CI)0.72 [0.66, 0.79]
17.1 No cardiovascular disease513766Risk Ratio (IV, Random, 95% CI)0.60 [0.46, 0.79]
17.2 Cardiovascular disease822267Risk Ratio (IV, Random, 95% CI)0.76 [0.71, 0.81]
18 Sensitivity analysis: all-cause mortality1028276Risk Ratio (IV, Random, 95% CI)0.79 [0.69, 0.91]
18.1 No cardiovascular disease37215Risk Ratio (IV, Random, 95% CI)0.63 [0.44, 0.90]
18.2 Cardiovascular disease721061Risk Ratio (IV, Random, 95% CI)0.83 [0.75, 0.92]
19 Sensitivity analysis: fatal and non-fatal myocardial infarction89018Risk Ratio (IV, Random, 95% CI)0.55 [0.42, 0.72]
19.1 No cardiovascular disease47519Risk Ratio (IV, Random, 95% CI)0.54 [0.38, 0.76]
19.2 Cardiovascular disease41499Risk Ratio (IV, Random, 95% CI)0.56 [0.36, 0.90]
20 Sensitivity analysis: cardiovascular mortality719059Risk Ratio (IV, Random, 95% CI)0.77 [0.69, 0.87]
20.1 No cardiovascular disease1304Risk Ratio (IV, Random, 95% CI)0.37 [0.01, 8.90]
20.2 Cardiovascular disease618755Risk Ratio (IV, Random, 95% CI)0.77 [0.69, 0.87]
Analysis 1.1.

Comparison 1 Statins versus placebo or no treatment, Outcome 1 Major cardiovascular events.

Analysis 1.2.

Comparison 1 Statins versus placebo or no treatment, Outcome 2 All-cause mortality.

Analysis 1.3.

Comparison 1 Statins versus placebo or no treatment, Outcome 3 Cardiovascular mortality.

Analysis 1.4.

Comparison 1 Statins versus placebo or no treatment, Outcome 4 Fatal and non-fatal myocardial infarction.

Analysis 1.5.

Comparison 1 Statins versus placebo or no treatment, Outcome 5 Fatal and non-fatal stroke.

Analysis 1.6.

Comparison 1 Statins versus placebo or no treatment, Outcome 6 End-stage kidney disease.

Analysis 1.7.

Comparison 1 Statins versus placebo or no treatment, Outcome 7 Elevated creatine kinase (rhabdomyolysis).

Analysis 1.8.

Comparison 1 Statins versus placebo or no treatment, Outcome 8 Elevated liver enzymes.

Analysis 1.9.

Comparison 1 Statins versus placebo or no treatment, Outcome 9 Withdrawal due to adverse events.

Analysis 1.10.

Comparison 1 Statins versus placebo or no treatment, Outcome 10 Cancer.

Analysis 1.11.

Comparison 1 Statins versus placebo or no treatment, Outcome 11 End of treatment creatinine clearance (CrCl).

Analysis 1.12.

Comparison 1 Statins versus placebo or no treatment, Outcome 12 End of treatment proteinuria.

Analysis 1.13.

Comparison 1 Statins versus placebo or no treatment, Outcome 13 Total cholesterol.

Analysis 1.14.

Comparison 1 Statins versus placebo or no treatment, Outcome 14 LDL cholesterol.

Analysis 1.15.

Comparison 1 Statins versus placebo or no treatment, Outcome 15 HDL cholesterol.

Analysis 1.16.

Comparison 1 Statins versus placebo or no treatment, Outcome 16 Triglycerides.

Analysis 1.17.

Comparison 1 Statins versus placebo or no treatment, Outcome 17 Sensitivity analysis: major cardiovascular events.

Analysis 1.18.

Comparison 1 Statins versus placebo or no treatment, Outcome 18 Sensitivity analysis: all-cause mortality.

Analysis 1.19.

Comparison 1 Statins versus placebo or no treatment, Outcome 19 Sensitivity analysis: fatal and non-fatal myocardial infarction.

Analysis 1.20.

Comparison 1 Statins versus placebo or no treatment, Outcome 20 Sensitivity analysis: cardiovascular mortality.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. pre-dialy* or predialy*:ti,ab,kw in Clinical Trials

  2. MeSH descriptor Kidney Diseases, this term only

  3. chronic kidney*:ti,ab,kw in Clinical Trials

  4. chronic renal*:ti,ab,kw in Clinical Trials

  5. MeSH descriptor Renal Insufficiency, this term only

  6. MeSH descriptor Renal Insufficiency, Chronic explode all trees

  7. (CKF or CKD or CRF or CRD):ti,ab,kw in Clinical Trials

  8. ur?emi*:ti,ab,kw in Clinical Trials

  9. MeSH descriptor Uremia explode all trees in Clinical Trials

  10. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9)

  11. MeSH descriptor Hydroxymethylglutaryl-CoA Reductase Inhibitors explode all trees

  12. hydroxymethylglutaryl-CoA reductase inhibitor*:ti,ab,kw in Clinical Trials

  13. HMG CoA reductase inhibitor*:ti,ab,kw in Clinical Trials

  14. HMG Co A reductase inhibitor*:ti,ab,kw in Clinical Trials

  15. statin*:ti,ab,kw in Clinical Trials

  16. atorvastatin:ti,ab,kw or cerivastatin:ti,ab,kw or dalvastatin:ti,ab,kw or fluindostatin:ti,ab,kw in Clinical Trials

  17. fluvastatin: ti,ab,kw or simvastatin:ti,ab,kw or lovastatin:ti,ab,kw or pitavastatin:ti,ab,kw in Clinical Trials

  18. pravastatin:ti,ab,kw or rosuvastatin:ti,ab,kw or simvastatin:ti,ab,kw in Clinical Trials

  19. meglutol:ti,ab,kw or mevinolin:ti,ab,kw or monacolin:ti,ab,kw or pravachol:ti,ab,kw or lipex:ti,ab,kw or lipitor:ti,ab,kw or zocor:ti,ab,kw or mevacor:ti,ab,kw or lescol:ti,ab,kw or baycol:ti,ab,kw in Clinical Trials

  20. (#11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19)

  21. (#10 AND #20)

MEDLINE
  1. Renal Insufficiency/

  2. exp Renal Insufficiency, Chronic/

  3. Kidney Diseases/

  4. (chronic kidney or chronic renal).tw.

  5. (CKF or CKD or CRF or CRD).tw.

  6. (predialysis or pre-dialysis).tw.

  7. exp Uremia/

  8. ur$emi$.tw.

  9. (pre-dialy$ or predialy$).tw.

  10. or/1-9

  11. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/

  12. "hydroxymethylglutaryl-CoA reductase inhibitor$".tw.

  13. ("HMG CoA reductase inhibitor$" or "HMG Co A reductase inhibitor$").tw.

  14. statin$.tw.

  15. atorvastatin.tw.

  16. cerivastatin.tw.

  17. dalvastatin.tw.

  18. fluindostatin.tw.

  19. fluvastatin.tw.

  20. lovastatin.tw.

  21. pitavastatin.tw.

  22. pravastatin.tw.

  23. rosuvastatin.tw.

  24. simvastatin.tw.

  25. (meglutol or mevinolin$ or monacolin$ or pravachol or lipex or lipitor or zocor or mevacor or lescol or baycol).tw.

  26. or/11-25

  27. and/10,26

EMBASE
  1. Kidney Disease/

  2. Chronic Kidney Disease/

  3. Kidney Failure/

  4. Chronic Kidney Failure/

  5. Kidney dysfunction/

  6. (chronic kidney or chronic renal).tw.

  7. (CKF or CKD or CRF or CRD).tw.

  8. (pre-dialy$ or predialy$).tw.

  9. or/1-8

  10. exp Hydroxymethylglutaryl Coenzyme a Reductase Inhibitor/

  11. hydroxymethylglutaryl-CoA reductase inhibitor$.tw.

  12. HMG CoA reductase inhibitor$.tw.

  13. HMG Co A reductase inhibitor$.tw.

  14. statin$.tw.

  15. atorvastatin.tw.

  16. cerivastatin.tw.

  17. dalvastatin.tw.

  18. fluindostatin.tw.

  19. fluvastatin.tw.

  20. lovastatin.tw.

  21. pitavastatin.tw.

  22. pravastatin.tw.

  23. rosuvastatin.tw.

  24. simvastatin.tw.

  25. (meglutol or mevinolin$ or monacolin$ or pravachol or lipex or lipitor or zocor or mevacor or lescol or baycol).tw.

  26. or/10-25

  27. and/9,26

Appendix 2. Risk of bias assessment tool

Potential source of bias Assessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence

Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).
High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.
Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment

Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).
High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.
Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study

Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.

Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.
High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.
Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.

Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.
High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.
Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting

Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table

Low risk of bias: The study appears to be free of other sources of bias.
High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.
Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.

Feedback

Review conclusions (2009 review)

Summary

Navaneethan SD et al (Navaneethan 2009¹) in their systematic review titled ‘HMG CoA reductase inhibitors (statins) for people with chronic kidney disease (CKD) not requiring dialysis’ came to the conclusion that “statins cause a significant reduction in the risk of all-cause mortality and cardiovascular mortality in CKD patients who are not requiring dialysis.” We feel that this claim requires reassessment based on the following reasons.

For the outcome all-cause mortality, the review included 21 ‘individual’ studies. The results of this outcome were driven (99%) by a pooling of three individual studies (LIPID², CARE³ and WOSCOPS⁴). These three trials were included as one entry (PPP 2004⁵) in the forest plot (analysis 1.1). The pooling of these three trials is incorrect in a meta-analysis as it gives improper weighting to the data. Inappropriate pooling of data as one study can negatively impact the weight and precision that would be apparent had these trials been entered as separate studies. The review explained that the reason for pooling the trials is that they could not get the data in a separate form. This however, is not a sufficient reason to pool the trials together as one. Also, the review references the subgroup analysis of CARE, where the individual data is reported separately. We would like to know the attempts that were made to obtain individual trial data and see this in an updated review.

Secondly, we are concerned with how studies were identified and included in this review. While the PPP makes up 99% of the all-cause mortality data, we are aware of many other statin trials with mortality data. For example, the Heart Protection Study (HPS 2003) was included in non-fatal CV events (analysis 1.3), but not for all-cause or cardiovascular mortality. We are unclear as to the efforts that were made to obtain subgroup data on kidney disease patients from all of the statin trials published. We have the same concern as above with respect to those studies that were excluded from this review. Figure 1 provides a flow diagram of the number of trials excluded, however the authors do not describe in detail the reasons for exclusion.

Third, the PPP publication separates individuals into normal, mild and moderate kidney disease (GFR 30-59.99 mL/min/1.73m²). According to this paper, the total amount of patients that would meet the inclusion criteria of this Cochrane review (that is moderate kidney disease) would be 4,491, instead of the 16,824 that were actually analysed. This means that there were approximately an extra ˜12,000 patients included in this review that who not actually meet the inclusion criteria of moderate kidney disease. We would like to know what efforts were made to extract this data and what process was done to see if the extra 12,000 patients fit the other inclusion criteria of this Cochrane review (i.e. some form of kidney disease, but normal renal function, elevated baseline serum creatinine). Upon review of two of the individual trials, we could not find any indication for inclusion of the patient data in this Cochrane review based on what was reported in the publications.

With respect to serious adverse events, this review does not specifically address all of the potential harms associated with statins. The Cholesterol Treatment Trialists’ (CTT) collaboration⁶ report an increased risk of hemorrhagic stroke with statin use, with high dose vs. low dose and compared to control. This increase although not statistically significant, is a concern of statin use that should be addressed when considering the benefit and risk of this class of medications.

Two of the three trials included (LIPID and CARE) were secondary prevention trials. That is, patients whom had already experienced an event (e.g. myocardial infarction, stroke). The benefit of statins in secondary prevention, irrespective of CKD has already been well established. The authors do outline that they were including patients with or without coronary artery disease, however the bigger question that remains unanswered is there any benefit of statins in a primary prevention patient with CKD. The SHARP⁷ trial aimed to answer this question in a dialysis and non-dialysis population, and found no reduction in all-cause mortality or cardiovascular mortality. Including both primary and secondary prevention trials together can bias the end result in favour of treatment for the entire population, when in fact the benefit may only exist in secondary prevention patients. Given the above issues, we cannot be certain of the benefit that is claimed for statins in non-dialysis CKD patients.

We hope this provides some constructive feedback for the next review. We look forward to hearing from you.

Sincerely,

Megan Harbin, BSc.Pharm, Pharmacy Resident

Anthony Amadio, BSc.Pharm, ACPR, PharmD Student

Aaron Tejani, BSc.Pharm, PharmD

The authors of this letter have no known conflicts of interest to declare.

References:

  1. Navaneethan SD, Pansini F, Perkovic V, Manno C, Pellegrini F, Johnson DW, Craig JC, Strippoli GFM. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD007784. DOI: 10.1002/14651858.CD007784.

  2. Anonymous. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group.[see comment]. New England Journal of Medicine 1998;339(19): 1349–57.

  3. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G, Cholesterol and Recurrent Events (CARE) Trial Investigators. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency. Annals of Internal Medicine 2003;138 (2):98–104.

  4. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. New England Journal of Medicine 1995; 333(20):1301–7

  5. Tonelli M, et al. Effect of Pravastatin on Cardiovascular Events in People with Chronic Kidney Disease. Circulation 2004;110:1557-1563.

  6. Baigent C, Blackwell L, Emberson J et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376(9753):1670-1681.

  7. Baigent C, Landray MJ, Reith C, et al, on behalf of the SHARP Investigators. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011; 377: 2181–92.

Reply

Dear Ms.Harbin,

We like to thank you for your careful review of our Cochrane systematic review titled- HMG CoA reductase inhibitors for people with chronic kidney disease not requiring dialysis published in 2009. Please see our responses below which answers your specific concerns:

Pooling of Pravastatin Pooling Project with other studies: We obtained additional unpublished data for the Pravastatin pooling project from Dr. Tonelli (email communication by Dr. Strippoli). As discussed in the review, we attempted to obtain individual trial data but without success. An updated systematic review that examined the use of statins in patients with varying severity of kidney disease was published in 2012 (Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Ann Intern Med. 2012 Aug 21;157(4):263-75). This review included additional studies and reported results separately for those who were on dialysis, received renal transplant and those who had non-dialysis dependent CKD. Cochrane reviews get updated every 2-3 years to include any new studies that gets published. Update of our 2009 Cochrane review is in press (to be published in late 2013) and clarify some other issues pointed out by you.

Inclusion of other studies with CKD sub-groups: Thanks for pointing out this. We have included the Heart Protection Study and other trials that provided data relating to those with CKD in the updated review (Palmer SC et al. Annals of Internal Medicine 2012) and the upcoming Cochrane Review. In the updated Cochrane review (in Press), reasons for exclusion were provided in Figure 1.

Confirmation of CKD: We reported the total number of patients included in the studies and agree that not all participants had CKD and only 4491/19700 patients in the Pravastatin Pooling Project had CKD. We did not have access to the original data for this study precluding us to assess whether others had any other forms of kidney disease (such as dialysis or renal transplant). These could be addressed by an individual patient-level meta-analysis that could be considered by other investigators in future.

Inclusion of stroke as an adverse event: We extracted details relating to adverse events from all individual studies. Even though few trials reported increased incidence of stroke in dialysis population, there was no increased risk for this subgroup (RR, 0.61 [CI, 0.38 to 0.98]) (Palmer SC et al. Annals of Internal Medicine 2012). These data were not included in the 2009 Cochrane Review but will be available in the update Cochrane review.

Statins for primary vs. secondary prevention: This important issue that has been discussed in the literature (Erickson et al. J Am Coll Cardiol. 2013 Mar 26;61(12):1250-8 and Massy et al. Kidney Int. 2013 Sep;84(3):451-6 and Updhyay et al Ann Intern Med. 2012 Aug 21;157(4):251-62.). CKD population have significant CV disease burden with higher coronary events (Tonelli M et al. Lancet 2012 Sep 1;380(9844):807-14) arguing for the use of statins as a primary prevention measure. As you pointed out, SHARP trial reported a statistically significant reduction in atherosclerotic events (primary outcome measure) but no significant reduction in the individual secondary end-points. Given the limited data available relating to primary and secondary prevention with statins in CKD, primary and secondary prevention trials were pooled together in our review.

In summary, we agree with some of the issues raised by you and your team members. We have added additional details suggested by you in the updated Cochrane review (in press) and in the paper published in Annals of Internal Medicine (Palmer SC et al. 2012). However, we do have several unanswered questions that might be addressed in future clinical trials to better treat our patients. Once again, thank you for the constructive feedback.

Sincerely,

Sankar Navaneethan, MD, MPH,

Suetonia Palmer, MBChB, PhD

Giovanni Strippoli MD, MM, MPH, PhD.

Contributors

Megan Harbin, BSc.Pharm, Pharmacy Resident

Anthony Amadio, BSc.Pharm, ACPR, PharmD Student

Aaron Tejani, BSc.Pharm, PharmD

Sankar Navaneethan, MD, MPH,

Suetonia Palmer, MBChB, PhD

Giovanni Strippoli MD, MM, MPH, PhD.

What's new

DateEventDescription
8 July 2014AmendedSources of external support amended
7 July 2014AmendedDeclarations of interests amended

History

Protocol first published: Issue 2, 2009
Review first published: Issue 2, 2009

DateEventDescription
10 June 2014Feedback has been incorporatedFeedback on original review incorporated
9 May 2014New citation required and conclusions have changedNew studies included
9 May 2014New search has been performedMethods updated, new authors, new search preformed
4 March 2012AmendedAuthor added (SP) and contact details updated.
1 March 2012New search has been performedUpdated search to February 2012. 24 new trials included (14,803 additional participants). Results and conclusions updated. Conclusions generally unchanged.
13 May 2009AmendedContact details updated.
3 July 2008AmendedConverted to new review format.

Contributions of authors

  • Suetonia C Palmer: Data extraction, analysis and interpretation, drafting the updated manuscript, final approval of version to be published

  • Sankar D Navaneethan: Concept and design of the review, data extraction, analysis and interpretation of data, writing the final manuscript, final approval of version to be published

  • Vlado Perkovic: Critical revision for intellectual content, interpretation of data, assistance with writing of the final manuscript, final approval of the manuscript to be submitted for publication

  • David W Johnson: Data extraction, analysis and interpretation of data, writing the final manuscript, final approval of version to be published

  • Jonathan Craig: Concept and design, analysis and interpretation of data, writing the final manuscript, final approval of version to be published

  • Giovanni FM Strippoli: Concept and design of the review, data extraction, analysis and interpretation of data, writing the final manuscript, final approval of version to be published

Declarations of interest

Jonathan Craig: nothing to declare

Jorgen Hegbrant: nothing to declare

David Johnson: nothing to declare

Sankar Navaneethan: nothing to declare

Suetonia Palmer: nothing to declare

Vlado Perkovic: has received speakers fees from Astra Zeneca. His employer has participated in a clinical trial of statins, that was funded by an unrestricted grant from Merck Schering Plough to the University of Oxford

Giovanni Strippoli: nothing to declare.

Differences between protocol and review

We did not include studies with follow up of less than eight weeks duration (excluding data from Van Dijk 2001) in the 2014 review update.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

4S 1993

Methods
  • Study design: double-blinded placebo-controlled RCT

  • Study duration: 1988 to 1994

  • Follow-up period: 5.4 years

Participants
  • Country: Scandinavian countries

  • Setting: international, multicentre (94)

  • Patient records of men and women aged 35 to 70 years with history of angina pectoris or AMI; eGFR < 75 mL/min/1.73 m²

  • Number: treatment group (1143); control group (1171)

  • Mean age ± SD (years): treatment group (60.6 ± 6.1); control group (60.3 ± 6.2)

  • Sex (M/F): treatment group (846/297); control group (850/321)

  • Exclusion criteria: premenopausal women of childbearing potential; secondary hypercholesterolaemia; unstable or Prinzmetal angina; tendon xanthomata; planned coronary artery surgery or angioplasty; MI during the preceding 6 months; antiarrhythmic therapy; CHF requiring treatment with digitalis; diuretics, or vasodilators; persistent atrial fibrillation; cardiomegaly; haemodynamically important valvular heart disease; history of completed stroke; impaired hepatic function; partial ileal bypass; history of drug or alcohol abuse; poor mental function; other serious disease; current treatment with another investigational drug; hypersensitivity to statins

Interventions

Treatment group

  • Simvastatin: 20 mg titrated to 40 mg if needed to decrease total cholesterol levels to < 200 mg/dL

Control group

  • Placebo

Outcomes
  • Total mortality

  • Major coronary events, including coronary deaths, definite or probable hospital verified non-fatal acute MI, resuscitated cardiac arrest, and definite silent MI verified by ECG

  • Any coronary event, i.e. the secondary endpoint events plus myocardial revascularisation procedures and hospital admission for acute CHD events without a diagnosis of MI (mainly prolonged chest pain)

  • Death or any atherosclerotic event (coronary, cerebrovascular, and peripheral), i.e. death from any cause and events included under the first tertiary end-point plus hospital-verified non-fatal coronary atherosclerotic events

  • Incidence of myocardial revascularisation procedures, either coronary artery bypass grafting or percutaneous transluminal coronary angioplasty

  • Incidence of hospital admission for acute CHD events without MI diagnosis

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskRandomisation by sequential assignment of allocation numbers for which the pre-packaged test medication had been prepared according to the randomisation code. Patients who qualified for the study on the basis of a previous MI were assigned allocation numbers beginning with the lowest allocation number available for each respective centre; patients who qualified on the basis of angina only were assigned allocation numbers starting with the highest number available. Randomisation was made in separate blocks for each centre. The block size was unknown to the investigators
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe Scandinavian Simvastatin Survival Study (4S) was a multicentre, double-blind (triple-blind because patients, investigators and study administration were unaware of patients’ drug assignment), randomised, placebo-controlled study with simvastatin
Blinding of outcome assessment (detection bias)
All outcomes
Low risk4S was a multicentre, double-blind (triple-blind because patients, investigators and study administration were unaware of patients’ drug assignment), randomised, placebo-controlled study with simvastatin
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted for in the analysis; all data analysed by intention-to-treat (ITT)
Other biasHigh riskFunding: supported by a grant from Merck Research Laboratories, Rahway, NJ

AFCAPS/TexCAPS 1997

Methods
  • Study design: double-blind, placebo-controlled RCT

  • Study duration: NR

  • Follow-up period: 5.1 years

Participants
  • Country: USA

  • Setting: multicentre

  • Men and women with normal to mildly elevated cholesterol and reduced HDL defined as TC 180 to 264 mg/dL, LDL 130 to 190 mg/dL, HDL < 45 mg/dL for men, and > 47 mg/dL for women, TG > 400 mg/dL

  • Number: treatment group (145); control group (159)

  • Mean age ± SD (years): treatment group (62 ± 8.0); control group (62 ± 7.0)

  • Sex (M/F): treatment group (119/26); control group (120/39)

  • Exclusion criteria: prior MI history; angina; claudication; CVA; or TIA; aged > 73 or > 45 years (men) or > 55 years (women) or those with secondary hyperlipoproteinaemia; nephrotic syndrome; uncontrolled or insulin-dependent DM; or uncontrolled hypertension

Interventions

Treatment group

  • Lovastatin: 20 mg dose titrated to 40 mg if LD > 110 mg/dL

Control group

  • Placebo

Outcomes
  • Rate of first acute major coronary events (i.e. sudden cardiac death, fatal and non-fatal MI, and unstable angina)

  • Fatal and non-fatal coronary revascularisation procedures

  • Unstable angina

  • Fatal and non-fatal MI

  • Fatal and non-fatal cardiovascular events

  • Fatal and non-fatal coronary events

  • Cardiovascular mortality

  • CHD mortality

  • Total mortality

  • Non-cardiovascular mortality (with subset analyses for accidental/violent death and death from cancer)

  • Fatal and non-fatal cancer (excluding basal cell and squamous cell skin cancers)

  • Discontinuation for adverse drug effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskAFCAPS/TexCAPS was a double blind, randomised, placebo-controlled study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskParticipants, investigators, Steering Committee members, and those providing participant care, monitoring or managing data, or adjudicating end points were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskDetails of study withdrawals provided, all analyses were based on ITT basis
Other biasHigh risk'Mr Cook is an employee of Merck & Co Inc, which markets lovastatin'. 'This study was funded by an Amgen fellowship grant.'

ALLIANCE Study 2000

Methods
  • Study design: open-label RCT

  • Study duration: 1995 to 2002

  • Follow-up period: 54.3 months

Participants
  • Country: USA

  • Setting: multicentre (16)

  • Men or women aged ≥ 18 years with known CHD, defined as prior acute MI, percutaneous coronary intervention, CABG, or unstable angina

  • Number: treatment group (286); control group (293)

  • Mean age ± SD (years): treatment group (65.6 ± 7.4); control group (64.8 ± 7.0)

  • Sex (M/F): treatment group (217/69); control group (228/65)

  • Exclusion criteria: breastfeeding or pregnancy; women of childbearing age who planned to become pregnant during the study; women who did not practice birth control methods considered acceptable to the investigator; any significant abnormalities the investigator believed may compromise patient safety or successful completion of the study; any disease process likely to limit life to less than the duration of the study; all cancers (excluding basal cell and squamous cell skin cancers); New York Heart Association class III or IV CHF; and known hypersensitivities to hydroxymethylglutaryl coenzyme A reductase inhibitors (statins)

Interventions

Treatment group

  • Atorvastatin: started at 10 mg/d and doubled every 4 weeks until patients achieved LDL cholesterol level goal < 80 mg/dL or were receiving a maximum dose of 80 mg/d

Control group

  • Usual care patients were maintained on the lipid-lowering program to which they were already prescribed

Outcomes
  • Time from randomisation to first occurrence of a primary cardiovascular event, including cardiac death, non-fatal MI, resuscitated cardiac arrest, cardiac revascularisation, and unstable angina requiring hospitalisation

  • All-cause mortality

  • Peripheral revascularisation

  • Hospitalisation for CHF

  • Stroke

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
Low riskLost to follow-up details reported, ITT analysis performed for all randomised patients
Other biasHigh riskSupport: This study was sponsored initially by Parke-Davis and later by Pfizer Inc. Editorial support was provided by Mr Steve Dobson and Dr Shirley Smith at Envision Pharma Ltd and funded by Pfizer Inc.
Financial disclosure: Dr Koren has received research support from Pfizer Inc, Merck, AstraZeneca, Novartis, and Merck/Schering-Plough and consulting fees from Pfizer Inc. Dr Davidson has received research support from Pfizer Inc, Merck, AstraZeneca, and Merck/Schering-Plough and consulting
fees from Merck, AstraZeneca, and Merck/Schering-Plough and has served on speaker bureaus for Pfizer Inc, Merck, AstraZeneca, and Novartis. Drs Wilson, Fayyad, Zuckerman, and Reed are employees of Pfizer Inc. Pfizer Inc is the manufacturer of Lipitor, a proprietary version of atorvastatin.

Aranda 1994

Methods
  • Study design: open-label RCT

  • Study duration: NR

  • Follow-up period: NR

Participants
  • Country: Spain

  • Setting: single centre

  • Proteinuria > 2 g/d, CrCl > 30 mL/min, LDL > 190 mg/dL

  • Number: treatment group (8); control group (8)

  • Mean age ± SD (years): treatment group (57 ± 6); control group (47 ± 6)

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Hypolipaemic diet

  • Pravastatin: 20 to 40 mg

Control group

  • Placebo

Outcomes
  • CrCl

  • proteinuria

  • Lipid parameters (TC, LDL, HDL, TG)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

ASCOT-LLA 2003

Methods
  • Study design: double blind RCT

  • Study duration: NR

  • Follow-up period: 3.2 years

Participants
  • Country: UK, Ireland and Nordic countries

  • Setting: multicentre

  • Men and women aged from 40 to 79 years at randomisation, with either untreated hypertension, defined as SBP ≥ 160 mm Hg, DBP ≥100 mm Hg, or both, or treated hypertension with SBP ≥ 140 mm Hg, DBP ≥ 90 mm Hg, or both. Patients had to be eligible for the blood pressure-lowering arm, have TC concentrations ≤ 6.5 mmol/L, and not currently be taking a statin or a fibrate

  • Number: 10,305

  • Mean age ± SD (years): NR

  • Sex (M/F): NR

  • Exclusion criteria: previous MI; currently treated angina; a cerebrovascular event within the previous 3 months; fasting TG > 4.5 mmol/L; heart failure; uncontrolled arrhythmias or any clinically important haematological or biochemical abnormality on routine screening

Interventions

Treatment group

  • Atorvastatin

Control group

  • Placebo

Outcomes
  • All-cause mortality

  • CV mortality

  • Stroke

  • Coronary events (MI, revascularisation)

  • Lipid profile (TC, LDL, HDL, TG)

NotesData available only in abstract form
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskInvestigators submitted all information relevant to any potential endpoints to the coordinating centre for central review of endpoints by the endpoint committee, who were unaware of treatment assignment
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Bianchi 2003

Methods
  • Study design: open-label RCT

  • Study duration: NR

  • Follow-up period: 12 months

Participants
  • Country: Italy, USA

  • Setting: international, multicentre (2)

  • Hypercholesterolaemia; mild-to-moderate CKD and proteinuria (idiopathic chronic glomerulonephritis)

  • Number: treatment group (28); control group (28)

  • Mean age ± SD (years): treatment group (56.5 ± 1.5); control group (56.8 ± 1.5)

  • Sex (M/F): treatment group (19/9); control group (19/9)

  • Exclusion criteria: DM; renovascular or malignant hypertension; secondary glomerular disease; malignancies; MI or CVA in the 6 months preceding the study; CHF; hepatic dysfunction; neuromuscular disorders; history of allergy to ACEi, ARB and statins

Interventions

Treatment group

  • Atorvastatin: maximum dose 40 mg/d (target LDL < 120 mg/dL or 40% reduction compared with baseline values)

Control group

  • Placebo

Outcomes
  • Proteinuria

  • Lipid profile (TC, LDL, HDL, TG)

  • Kidney function (CrCl)

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskControlled, prospective, open-label study
Blinding of outcome assessment (detection bias)
All outcomes
High riskControlled, prospective, open-label study
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Buemi 2000

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 6 months

Participants
  • Country: Italy

  • Setting: single centre

  • IgA nephropathy with TC < 6.73 mmol/L and no cholesterol-lowering therapy in the previous year

  • Number: treatment group (13); control group (8)

  • Mean age, range (years): treatment group (36, 35 to 41); control group (38, 30 to 45)

  • Sex (M/F): treatment group (8/5); control group (5/3)

  • Exclusion criteria: DM; severe hypertension; kidney failure (SCr > 1.8 mg/dL); tobacco smoking; alcoholism

Interventions

Treatment group

  • Fluvastatin: 40 mg/d

Control group

  • Placebo

Outcomes
  • Proteinuria and albuminuria

  • Lipid profile

  • Kidney function (CrCl)

  • Histological features

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

CARDS 2003

Methods
  • Study design: placebo-controlled RCT

  • Study duration:1997 to 2001

  • Follow-up period: 4 years

Participants
  • Country: UK, Ireland

  • Setting: multicentre

  • Patients with DM and at least 1 of the following risk factors:

    • history of hypertension

    • retinopathy (i.e. any retinopathy, maculopathy, or prior photocoagulation)

    • microalbuminuria or macroalbuminuria

    • current smoking

  • Number: treatment group (482); control group (488)

  • Mean age ± SD (years): treatment group (65.0 ± 6.7); control group (65.0 ± 6.7)

  • Sex (M/F): treatment group (233/249); control group (232/256)

  • Exclusion criteria: History of MI, angina, coronary vascular surgery, CVA, or severe peripheral vascular disease (defined as warranting surgery), SCr > 1.7 mg/dL or HbA1c> 12%

Interventions

Treatment group

  • Atorvastatin: 10 mg

Control group

  • Placebo

Outcomes
  • Acute CHD event (MI including silent infarction, unstable angina, acute CHD death, resuscitated cardiac arrest), coronary revascularisation procedures, or stroke)

  • Total mortality

  • Any acute, hospital-verified cardiovascular endpoint

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskWithin every centre, the local investigator sequentially randomly assigned eligible patients to study treatment (either placebo or atorvastatin 10 mg daily) from a block of drugs that had been prepackaged for every centre by Pfizer, according to a computer-generated randomisation code
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind placebo controlled
Blinding of outcome assessment (detection bias)
All outcomes
Low riskInvestigators, pharmacists, study administrators, and patients were unaware of the randomisation code throughout the study
Incomplete outcome data (attrition bias)
All outcomes
Low riskLost to follow-up was minimal, all analyses were ITT
Other biasLow riskFunding: this study was funded in part by the UK Department of Health and Diabetes UK

Di Lullo 2005

Methods
  • Study design: open-label parallel RCT

  • Study duration: June 2002 to June 2004

  • Follow-up period: 8 months

Participants
  • Country: Italy

  • Setting: single centre

  • Men and women aged from 18 to 80 years, with diagnosis of mild to moderate CKD (according to KDOQI guidelines) for at least 5 years: CrCl 45 to 55 mL/min (24 hour collection); CRP 3 to 14 mg/dL; TC 250 to 350 mg/dL; HDL 50 to 70 mg/dL; LDL 100 to 190 mg/dL; TG 160 to 450 mg/dL

  • Number: treatment group (80); control group (50)

  • Mean age (years): treatment group (59.4); control group (58.7)

  • Sex (M/F): 70/60

  • Exclusion criteria: patients with current diagnosis of severe heart failure (NYHA Class II–IV); familial hypercholesterolaemia; hypertriglyceridaemia; CrCl < 15 mL/min who were in dialysis

Interventions

Treatment group

  • Fluvastatin XL: 80 mg once daily

Control group

  • Placebo

Outcomes
  • CrCl

  • CRP

  • Lipid profile (TC, LDL, HDL, TG)

  • Adverse events: liver function and myotoxicity indices (ALT, AST, gamma glutamyltransferase, lactic dehydrogenase, and creatine phosphokinase)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NS

Dummer 2008

Methods
  • Study design: cross-over RCT

  • Study duration: March 2004 to 2006

  • Follow-up period: 8 weeks

Participants
  • Country: Brazil

  • Setting: single centre

  • Aged ≥ 18 years with stage 3 or 4 CKD classified according to KDOQI criteria

  • Number: 33

  • Mean age ± SD: 55.8 ± 15.3 years

  • Sex (M/F): 15/18

  • Exclusion criteria: acute or chronic inflammatory or infectious disease; any CV or cerebrovascular event in the last 3 months; need for RRT before or during the study period; receiving statins for secondary prevention of CV events; not sign the informed consent form

Interventions

Treatment group

  • Simvastatin: 20 mg

Control group

  • Placebo

Outcomes
  • GFR-MDRD formulae, proteinuria

  • Lipid profile (TC, LDL, HDL, TG)

  • Adverse events: liver function (ALT, AST, gamma glutamyltransferase) and myotoxicity indices (creatine phosphokinase)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskRandomised, placebo-controlled, double-blind, cross-over clinical study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant number of drop-outs; ITT not performed
Other biasLow riskFunding: financial support was received from the research Promotion Fund of the Hospital de Clinicas de Porto Alegre (FIPE-HCPA) The BIOLAB Pharma Laboratory provide the blinded simvastatin and placebo tablets

ESPLANADE Study 2010

Methods
  • Study design: open-label RCT

  • Study duration: NR

  • Follow-up period: 6 months

Participants
  • Country: Italy

  • Setting: multicentre (16)

  • Aged > 16 years, with SBP or DBP 140 or 90 mm Hg, respectively, or had concomitant antihypertensive therapy, and 24 hour proteinuria persistently 1 g (subsequently amended to 0.5 g to avoid unnecessary exclusion of a proportion of patients expected to have residual proteinuria 0.25 g despite dual RAS blockade) after 2 month washout from previous treatment with RAS inhibitors or statins, with variation in CrCl 30% over the last 3 months without evidence of UTI or heart failure

  • Number: treatment group (92); control group (94)

  • Mean age ± SD (years): treatment group (51.4 ± 13.9); control group (51.4 ± 13.9)

  • Sex (M/F): 113/73

  • Exclusion criteria: CrCl 20 mL/min/1.73 m², with LDL 190 mg/dL despite low cholesterol diet, or on chronic treatment with corticosteroids, NSAIDs, or immunosuppressive drugs; AMI or CVA in the 6 months preceding the study; SBP/DBP 220/115 mm Hg; renovascular disease; obstructive uropathy; DM type 1; vasculitis; cancer; serum AST concentrations 3 x ULN; chronic cough; history of poor tolerance or allergy to ACEi, ARB, or statins; drug or alcohol abuse; legal incapacity; pregnancy; breastfeeding; and ineffective contraception

Interventions

Treatment group

  • Fluvastatin

  • ACEI and ARB

Control group

  • ACEI and ARB

Outcomes
  • Lipid profile (TC, LDL, HDL, TG)

  • Adverse events: rhabdomyolysis, elevated liver enzymes

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk175/186 (94%) completed study; ITT not reported
Other biasLow riskFunding: supported by a grant from Regione Lombardia, Direzione Generale Sanita`, Milan (Italy) and Novartis Farma S.p.A., Varese (Italy). Novartis Pharma also supplied the benazepril (Cibacen), valsartan (Tareg), and fluvastatin (Lescol) tablets required for study conduction.
Novartis Pharma had no involvement in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Fassett 2010

Methods
  • Study design: open-label RCT

  • Study duration: NR

  • Follow-up period: 2 years

Participants
  • Country: Australia

  • Setting: multicentre

  • Confirmed ADPKD based on kidney ultrasound examination, positive family history and at all levels of kidney function and serum cholesterol levels

  • Number: treatment group (29); control group (20)

  • Mean age ± SD (years): treatment group (53 ± 15); control group (49 ± 12)

  • Sex (M/F): treatment group (12/17); control group (7/13)

  • Exclusion criteria: women of childbearing age and those participating in another investigational within 30 days

Interventions

Treatment group

  • Simvastatin: 10 mg/d

Control group

  • Placebo

Outcomes
  • Kidney function measured by MDRD formula

  • 24 hour CrCl and proteinuria

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated random number list
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded
Incomplete outcome data (attrition bias)
All outcomes
High risk49/60 (82%) completed study; ITT not conducted
Other biasLow riskFunding: supported by a grant from the Clifford Craig Medical Research Trust

Fried 2001

Methods
  • Study design: placebo controlled RCT

  • Study duration: NR

  • Follow-up period: 24 months

Participants
  • Country: USA

  • Setting: single centre

  • Diabetic patients without overt nephropathy with TC 100 to 160 mg/dL and no cholesterol lowering therapy in the previous year

  • Number: treatment group (19); control group (20)

  • Mean age ± SD (years): treatment group (33 ± 9.1); control group (31 ± 6.7)

  • Sex (M/F): treatment group (11/8); control group (11/9)

  • Exclusion criteria: prior CVD

Interventions

Treatment group

  • Simvastatin: 10 mg/d

Control group

  • Placebo

Outcomes
  • Albuminuria

  • Lipid profile

  • Adverse events

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation by an unblinded pharmacist using a randomly generated list
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant drop-outs at 1 year and 2 year follow-up; ITT not performed
Other biasHigh riskFunding: supported by a grant from Merck

Gheith 2002

Methods
  • Study design: RCT

  • Study duration: 1996 to 1998

  • Follow-up period: 12 months

Participants
  • Country: Egypt

  • Setting: multicentre (2)

  • Nephrotic syndrome (steroid resistant, dependent, or frequently relapsing); hypercholesterolaemia; while off all lipid lowering drugs and adhering to an appropriate diet for at least 4 weeks; SCr < 2 mg/dL; recent renal biopsy showing FSGS or MPGN and written consent

  • Number: treatment group (21); control group (22)

  • Mean age ± SD (years): treatment group (23.0 ± 13.3); control group (22.2 ± 9.5)

  • Sex (M/F): treatment group (9/12); control group (9/13)

  • Exclusion criteria: lesion other than GSFS and MPGN; hepatic disease; muscle disease; history of familial dyslipidaemia; DM; patients with normal cholesterol; SCr > 2 mg/dL; concurrent use of lipid-lowering agents

Interventions

Treatment group

  • Fluvastatin: 20 mg/d

Control group

  • No therapy

Outcomes
  • Lipid profile

  • Proteinuria

  • Serum albumin CrCl (mL/dL/min) changes

  • Glomerular sclerosis and interstitial fibrosis

  • Renal fat deposits

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High riskITT not performed
Other biasLow riskFunding: financially supported by the research unit of the Mansoura University

Goicoechea 2006

Methods
  • Study design: prospective RCT

  • Study duration: NR

  • Follow-up period: 6 months

Participants
  • Country: Spain

  • Setting: single centre

  • CKD with eGFR < 90 mL/min and > 15 mL/min

  • Number: treatment group (44); control group (19)

  • Mean age ± SD (years): treatment group (66.2 ± 13.6); control group (70.0 ± 14.3)

  • Sex (M/F): treatment group (27/17); control group (13/6)

  • Exclusion criteria: fasting serum LDL 100 mg/dL and 200 mg/dL; existence of liver, cardiovascular, infectious, or systemic disease unrelated to ESKD; history of vascular intervention, CHF, or MI within 3 months preceding enrolment

Interventions

Treatment group

  • Atorvastatin: 20 mg

Control group

  • Placebo

Outcomes
  • eGFR

  • Lipid profile (TC, LDL, HDL, TG)

  • Inflammatory and fibrinolysis parameters (CRP, IL-1beta, TNF-alpha, IL-6, serum fibrinogen, t-PA, PAI-1)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant discrepancy between number of patients enrolled and data reported; ITT not performed
Other biasUnclear riskFunding: NR

Hommel 1992

Methods
  • Study design: placebo-controlled RCT

  • Study duration: NR

  • Follow-up period: 12 weeks

Participants
  • Country: Denmark

  • Setting: single centre

  • Diabetic nephropathy; TC > 5.5 mmol/L; aged 18 to 50 years; SCr ≤ 200 µmol/L

  • Number: treatment group (12); control group (9)

  • Mean age ± SD (years): treatment group (41 ± 9); control group (35 ± 4)

  • Sex (M/F): treatment group (6/6); control group (6/3)

  • Exclusion criteria: TC ≤ 5.5 mmol/L; kidney transplantation; SCr ≥ 200 µmol/L; enrolment in other studies

Interventions

Treatment group

  • Simvastatin: 10 to 20 mg/d

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Lipoproteins

  • Urine albumin excretion

  • Kidney function (GFR)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded
Incomplete outcome data (attrition bias)
All outcomes
High risk5/21 patients were withdrawn from the study; ITT not performed
Other biasUnclear riskFunding: tablets supplied by Merck Sharpe and Dohme

HPS 2002

Methods
  • Study design:

  • Study duration: 1994 to 1997

  • Follow-up period: 60 months

Participants
  • Country: UK

  • Setting: multicentre

  • Diabetic nephropathy; TC > 5.5 mmol/L; aged 18 to 50 years; SCr ≤ 200 µmol/L

  • Number: NR

  • Mean age ± SD (years): NR

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Simvastatin 40 mg/d

Control group

  • Placebo

Outcomes
  • Mortality

  • Lipid profile

  • Coronary events, stroke, revascularisation, major vascular events

  • Kidney function

  • Adverse events: rhabdomyolysis; elevated liver enzymes

NotesSubgroup analysis of larger study conducted in general population
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA central randomisation service was telephoned which enabled the coordinating centre to conduct a final check of eligibility prior to randomisation, and to balance the randomisation with respect to important patient characteristics (in particular, eligibility criteria and other major prognostic factors) using a minimisation algorithm
Allocation concealment (selection bias)Low riskA central randomisation service was telephoned which enabled the coordinating centre to conduct a final check of eligibility prior to randomisation, and to balance the randomisation with respect to important patient characteristics (in particular, eligibility criteria and other major prognostic factors) using a minimisation algorithm
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskYes
Incomplete outcome data (attrition bias)
All outcomes
Low riskITT performed
Other biasUnclear riskFunding: funded by the UK Medical Research Council, the British Heart Foundation, Merck & Co (manufacturers of simvastatin), and Roche Vitamins Ltd (manufacturers of the vitamins).

IDEAL Study 2004

Methods
  • Study design: open-label, blinded RCT (PROBE design)

  • Study duration: 1999 to 2005

  • Follow-up period: 4.8 years

Participants
  • Countries: northern Europe

  • Setting: multicentre

  • Men and women aged ≤ 80 years with history of definite MI and who qualified for statin therapy according to national guidelines at the time of recruitment

  • Number: treatment group 1 (4439); treatment group 2 (4449)

  • Mean age ± SD (years): treatment group 1 (61.8 ± 9.5); treatment group 2 (61.6 ± 9.5)

  • Sex (M/F): treatment group 1 (3590/849); treatment group 2 (3597/852)

  • Exclusion criteria: any known contraindications to statin therapy; previous intolerance to statins in low or high doses; liver enzyme levels > 2 x ULN; pregnancy or breastfeeding; nephrotic syndrome; uncontrolled DM; uncontrolled hypothyroidism; plasma TG levels > 600 mg/dL (6.8 mmol/L); CHF (NYHA classification IIIb or IV); haemodynamically important valvular heart disease; GI conditions affecting absorption of drugs; treatment with other drugs that seriously affect statins pharmacokinetics; treatment with other lipid lowering drugs

Interventions

Treatment group 1

  • Atorvastatin: 80 mg daily

Treatment group 2

  • Simvastatin: 20 mg

Outcomes
  • Time to first occurrence of a major coronary event, defined as coronary death, hospitalisation for non-fatal acute MI, or cardiac arrest with resuscitation

  • Major CV events (any primary event plus stroke; diagnosis of stroke required evidence of a neurological deficit, usually localised, lasting 24 hours or until death, usually confirmed by diagnostic imaging)

  • Any CHD event (any primary event, any coronary revascularisation procedure, or hospitalisation for unstable angina)

  • Any cardiovascular event (any of the former plus hospitalisation with a primary diagnosis of CHF and peripheral arterial disease, defined as new clinical diagnosis or hospitalisation for such disease)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskStudy medication assigned via a central interactive voice response system (ClinPhone, Nottingham, England)
Allocation concealment (selection bias)Low riskAllocation numbers assigned in blocks of 24. Allocation was balanced by centre; no other stratification was used
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAn end-point classification committee blindly reviewed reports on potential end-points and adjudicated outcomes at regular meetings. All reports were first screened by an independent centre (Inveresk, Raleigh, NC) for blinding of treatment allocation
Incomplete outcome data (attrition bias)
All outcomes
Low riskNR; all analyses based on the ITT principle including all randomised patients
Other biasHigh riskFunding: Drs Lindahl and Fayyad are Pfizer employees. All other authors except Dr Holdaas have received Honoraria from Pfizer Inc. as steering committee members of IDEAL. This study was sponsored by Pfizer Inc.

Imai 1999

Methods
  • Study design: open-label RCT

  • Study duration: NR

  • Follow-up period: 6 months

Participants
  • Country: Japan

  • Setting: multicentre

  • Hypertensive patients with mild kidney dysfunction (SCr ≥ 1.2 mg/dL and < 2.5 mg/dL by Jaffe method or ≥ 0.9 mg/dL and < 2.2 mg/dL by enzymatic method)

  • Number: treatment group (32); control group (25)

  • Mean age ± SD (years): treatment group (58.5 ± 9.2); control group (49.5 ± 11.4)

  • Sex (M/F): treatment group (19/13); control group (13/12)

  • Exclusion criteria: nephrotic syndrome; familial hypercholesterolaemia; CHD; cerebrovascular disease; CKD due to collagen disease; pregnant women; nursing women; allergy to statin

Interventions

Treatment group

  • Pravastatin

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Kidney function (CrCl, SCr)

  • 24 h albuminuria

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
High riskA total of 62 participants were registered for the study. Five participants who did not conform to the criteria were excluded from the study after the study was completed. There were 57 patients entered into the analysis; ITT not performed
Other biasUnclear riskFunding: NR

JUPITER Study 2007

Methods
  • Study design: placebo controlled RCT

  • Study duration: 2003 to 2008

  • Follow-up period: Median 1.9 years

Participants
  • Country: 26 countries

  • Setting: international, multicentre

  • Men aged ≥ 50 years and women aged ≥ 60 years of age were eligible if they did not have CVD history, and if at initial screening LDL < 130 mg/dL (3.4 mmol/L) and a high sensitivity CRP ≥ 2.0 mg/L

  • Number: 3267

  • Mean age (range): 70 years (65.0 to 75.0)

  • Sex (M/F):1138/2129

  • Exclusion criteria: previous or current use of lipid-lowering therapy; current use of postmenopausal HRT; evidence of hepatic dysfunction (AST level > 2 x ULN); creatine kinase level > 3 x ULN; creatinine level > 2.0 mg/dL (176.8 μmol/L); DM; uncontrolled hypertension (SBP >190 mm Hg or DBP >100 mm Hg); cancer within 5 years before enrolment (exception basal cell or squamous cell carcinomas of the skin); uncontrolled hypothyroidism (TSH level > 1.5 x ULN); recent history of alcohol or drug abuse or another medical condition that might compromise safety or the successful completion of the study; inflammatory conditions such as severe arthritis, lupus, or inflammatory bowel disease; taking immunosuppressant agents such as cyclosporin, tacrolimus, azathioprine, or long-term oral glucocorticoids

Interventions

Treatment group

  • Rosuvastatin: 20 mg

Control group

  • Placebo

Outcomes
  • Occurrence of a first major cardiovascular event, defined as non-fatal MI, non-fatal stroke, hospitalisation for unstable angina, arterial revascularisation procedure, or confirmed death from cardiovascular causes

  • Components of the primary end-point considered individually

  • Arterial revascularisation or hospitalisation for unstable angina, MI, stroke, death from cardiovascular causes

  • All-cause mortality

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskRandomisation performed using an interactive voice-response system and stratified according to centre
Blinding of participants and personnel (performance bias)
All outcomes
Low riskRandomised, double-blind, placebo-controlled, multicentre study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll reported primary end-points that occurred to 30 March 2008 were adjudicated on the basis of standardised criteria by an independent end-point committee unaware of randomised
treatment assignments
Incomplete outcome data (attrition bias)
All outcomes
Low riskLost to follow-up was minimal, all primary analyses performed on ITT basis
Other biasHigh riskFunding: the JUPITER trial was supported by Astra-Zeneca; Dr. Cressman is an employee of AstraZeneca

Lam 1995

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 24 months

Participants
  • Country: Hong Kong

  • Setting: multicentre (2)

  • Mild to moderate hypercholesterolaemia (TC > 5.2 and < 7.8 mmol/L) and proteinuria > 0.15 g/d

  • Number: treatment group (16); control group (18)

  • Mean age ± SD (years): treatment group (58.9 ± 2.3); control group (53.9 ± 2.5)

  • Sex (M/F): treatment group (8/8); control group (11/7)

  • Exclusion criteria: NR

Interventions

Treatment group

  • Lovastatin: 20 mg/d

Control group

  • Placebo

Outcomes
  • Lipid profile

  • ApoA1, Apo (a), Apo B

  • BMI

  • HbA1c

  • Kidney function (GFR, SCr)

  • Proteinuria

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskSingle blinded study
Blinding of outcome assessment (detection bias)
All outcomes
High riskSingle blinded study
Incomplete outcome data (attrition bias)
All outcomes
High riskAll subjects accounted for in the main analysis; ITT not performed
Other biasUnclear riskFunding: NR

Lee 2002

Methods
  • Study design: parallel RCT

  • Study duration: NR

  • Follow-up period: 12 months

Participants
  • Country: Taiwan

  • Setting: single centre

  • Stable, well-controlled hypertension with seated DBP < 90 mm Hg and SBP 140 mm Hg at 3 months screening period

  • Number: treatment group (42); control group (40)

  • Mean age ± SD (years): treatment group (50 ± 9); control group (48 ± 8)

  • Sex (M/F): treatment group (29/13); control group (27/13)

  • Exclusion criteria: DM; secondary hypertension; kidney disease (SCr >1.5 mg/dL or 133 µmol/L) proteinuria (> 3 g/d); hyperlipidaemia (plasma TC > 240 mg/dL); treatment with corticosteroids or NSAIDs

Interventions

Treatment group

  • Pravastatin: 10 mg

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Kidney function (SCr, CrCl)

  • Proteinuria-urinary excretion of markers for glomerular size

  • Selectivity (IgG) and for proximal tubular function (retinol-binding protein)

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk3/63 (%) patients excluded; ITT not performed
Other biasLow riskFunding: Pravastatin was in part a generous gift from Sankyo Company, Limited, Tokyo, Japan. This work was supported by the grant of Chi-Mei Medical Center (CMFHT 9201, CMFHR9303, CMFHR9307, and CMTMU9305) and the grant of National Science Council, Republic of China (NSC 91-2314-B-384-008, NSC 91-2314-B-384-009, NSC92-2314-B-384-007, and NSC 92-2314-B-384-011)

Lintott 1995

Methods
  • Study design: placebo-controlled RCT

  • Study duration: NR

  • Follow-up period: 12 weeks

Participants
  • Country: New Zealand

  • Setting: single centre

  • Hyperlipidemic patients with plasma TC levels > 6.2 mmol/L and HDL-C < 0.90 mmol/L

  • Number: treatment group (32); control group (10)

  • Mean age ± SD (years): treatment group (57 ± 11); control group (63 ± 9)

  • Sex (M/F): treatment group (23/9); control group (8/2)

  • Exclusion criteria: active cardiac, GI, hepatic, or kidney disease (active kidney disease defined as > 10% decline in kidney function in the preceding 3 months); hypothyroidism, unless treated or stable; secondary hyperlipidaemia; MI or coronary bypass surgery within the previous 3 months; unstable angina

Interventions

Treatment group

  • Fluvastatin: 40 mg/day

Control group

  • Placebo

Outcomes
  • Lipid parameters (TC, LDL, HDL, TG)

  • Haemorheologic variables of plasma and whole blood viscosity, RBC deformability, and fibrinogen

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: Dr. Tony Cutten of Sandoz Pharma (New Zealand) for his support of this study

LIPS Study 2005

Methods
  • Study design:

  • Study duration: NR

  • Follow-up period: 3 to 4 years

Participants
  • Country: international

  • Setting: multicentre

  • One or more of the following

    • TC 135 to 270 mg/dL with fasting TG < 400 mg/dL

    • TC < 212 mg/dL for patients whose lipids levels were measured 24 hours to 4 weeks after MI episode

    • TC < 232 mg/dL for patients with DM

  • Number (kidney impairment): treatment group (150); control group (160)

  • Mean age ± SD (years): 69 ± 7

  • Sex (M/F): 208/102

  • Exclusion criteria: baseline SCr > 1.8 mg/dL

Interventions

Treatment group

  • Fluvastatin: 20 mg

Control group

  • Placebo

Outcomes
  • Cardiac death, non-fatal MI, coronary re-interventions not related to stenosis

  • Lipid profile

  • Kidney function

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskPatients were allocated to treatment in the order in which they were enrolled into the study at each centre according to medication pack numbers using block randomisation.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Low riskNR; ITT performed
Other biasHigh riskFunding: this study was supported by an industry grant (Novartis)

LORD Study 2006

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 2004 to 2008

  • Follow-up period: 2.5 years

Participants
  • Country: Australia

  • Setting: single centre

  • Aged 18 to 85 years, SCr > 120 μmol/L at screening visit, history of CKD

  • Number: treatment group (16); control group (18)

  • Mean age ± SD (years): treatment group (62.3 ± 16.3); control group (64.8 ± 15.0)

  • Sex (M/F): treatment group (9/7); control group (12/6)

  • Exclusion criteria: use of lipid-lowering medication; females of childbearing age, able to conceive and not using contraception; acute liver disease or unexplained persistent elevations of serum transaminases, or a history of alcoholism; history seizure within a year of study entry; hypersensitivity to atorvastatin or one of its components; participating in, or propose to participate in, another clinical investigational drug study within 30 days prior to study entry

Interventions

Treatment group

  • Atorvastatin: 10 mg

Control group

  • Placebo

Outcomes
  • Kidney function: eGFR (mL/min/1.73 m²/month) measured by MDRD and Cockcroft Gault equations, CrCl, SCr, proteinuria or albuminuria

  • Physical activity levels (Active Australia questionnaire)

  • Nutritional status (4 day diet diary)

  • Cardiovascular events and mortality

  • Hospital admissions

  • Drug safety and tolerability

  • Measures of inflammation (plasma C reactive protein, tumour necrosis factor-alpha and interleukin 6) and oxidative stress (plasma isoprostanes)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated random numbers
Allocation concealment (selection bias)Low riskA clinical research pharmacist independent of the trial used computer generated random numbers to conduct the randomisation
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk3/37 patients were excluded; ITT not performed
Other biasLow riskFunding: Clifford Craig Medical Research Trust is funding this study. Pfizer Pharmaceuticals
provided the atorvastatin and placebo

MEGA Study 2004

Methods
  • Study design: open-label RCT

  • Study duration: 1994 to 2004

  • Follow-up period: 5.3 years

Participants
  • Country: Japan

  • Setting:

  • Men and postmenopausal women aged 40 to 70 years with bodyweight ≥ 40 kg and hypercholesterolaemia (TC concentration 5.69 to 6.98 mmol/L)

  • Number (overall moderate CKD group): 2978

  • Mean age: 60 years

  • Sex (M/F): 745/2233

  • Exclusion criteria: familial hypercholesterolaemia and CHD or stroke history

Interventions

Treatment group

  • Pravastatin: 10 to 20 mg

Control group

  • Placebo

Outcomes
  • First occurrence of CHD, which included fatal and non-fatal MI, angina, cardiac and sudden death, and coronary revascularisation procedure

  • Stroke

  • CHD plus cerebral infarction

  • All cardiovascular events

  • Total mortality

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEligible patients were randomly assigned either diet or diet plus pravastatin by computerised randomisation by the permuted-block method
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll endpoints were reviewed strictly by the endpoint committee, without knowledge of treatment allocations, and additional information obtained from the physician as needed
Incomplete outcome data (attrition bias)
All outcomes
High risk102 participants lost to follow-up; statistical analyses done by ITT
Other biasLow riskFunding: none

Mori 1992

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 12 months

Participants
  • Country: Japan

  • Setting: single centre

  • Hyper and normocholesterolaemic patients with non-insulin dependent DM

  • Number: treatment group (18); control group (15)

  • Mean age ± SD (years): treatment group (62.0 ± 13.0); control group (64.1 ± 9.1)

  • Sex (M/F): treatment group (6/12); control group (6/9)

  • Exclusion criteria: NR

Interventions

Treatment group

  • Pravastatin: 10 mg/day

Control group

  • Placebo

Outcomes
  • Urinary albumin:creatinine ratio

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Nakamura 2002

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 6 months

Participants
  • Country: Japan

  • Setting: NR

  • Chronic GN and hypercholesterolaemia

  • Number: treatment group (20); control group (20)

  • Mean age ± SD (years): NR

  • Sex (M/F): NR

  • Exclusion criteria: heart disease; collagen disease; DM

Interventions

Treatment group

  • Cerivastatin: 0.15 mg/d

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Kidney function (SCr, CrCl)

  • Proteinuria urinary podocyte number

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Nakamura 2005

Methods
  • Study design: placebo-controlled RCT

  • Study duration: NR

  • Follow-up period: 12 months

Participants
  • Country: Japan

  • Setting: single centre

  • Patients with diabetic nephropathy

  • Number: treatment group (10); control group (10)

  • Mean age, range (years): treatment group (51, 42 to 60); control group (49, 44 to 58)

  • Sex (M/F): treatment group (6/4); control group (6/4)

  • Exclusion criteria: NR

Interventions

Treatment group

  • Pitvastatin: 1 mg/d

Control group

  • Placebo

Outcomes
  • Urinary liver-type fatty acid binding protein

  • Urinary albumin excretion

  • Total cholesterol

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskSealed envelope method
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Nakamura 2006

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 6 months

Participants
  • Country: Japan

  • Setting: single centre

  • Patients with mild CKD

  • Number: treatment group (15); control group (15)

  • Mean age ± SD (years): treatment group (39.5 ± 10.0); control group (40.5 ± 11.0)

  • Sex (M/F): treatment group (9/6); control group (9/6)

  • Exclusion criteria: hypertension (> 140/90 mm Hg) and kidney dysfunction (SCr 1 1.5 mg/dL or 24 h CrCl > 80 mL/min)

Interventions

Treatment group

  • Pitvastatin: 1 mg/d

Control group

  • Placebo

Outcomes
  • Urinary liver-type fatty acid binding protein

  • Urinary albumin excretion

  • TC, TG

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskSealed envelope method
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Nielsen 1993

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 36 weeks

Participants
  • Country: NR

  • Setting: NR

  • Persistent microalbuminuria; fasting levels of plasma cholesterol > 5.5 mmol/L; plasma TG < 4.5 mmol/L; HbA1c < 10%; fasting serum C-peptide > 0.49 mmol/L; BP < 160/95 mm Hg

  • Number: treatment group (8); control group (10)

  • Mean age ± SD (years): treatment group (65 ± 2); control group (65 ± 1 )

  • Sex (M/F): treatment group (6/2); control group (6/4)

  • Exclusion criteria: primary kidney, hepatic or insufficiently-treated cardiac disease

Interventions

Treatment group

  • Simvastatin: 10 to 20 mg/d

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Apo A1, A2, B

  • Kidney function (GFR)

  • Urinary albumin excretion

  • Glycaemic control

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High riskNot all patients accounted for in the analysis; ITT not performed
Other biasHigh riskFunding: this study was supported by Novo Nordisk Research Foundation, the Danish Medical Research Council, and Merck Sharp & Dohme

PANDA Study 2011

Methods
  • Study design: placebo-controlled RCT

  • Study duration: January 2005 to January 2009

  • Follow-up period: 36 months

Participants
  • Country: UK

  • Setting: Four hospital-based diabetic clinics

  • Age > 40 years; DM type 2 (WHO criteria); urinary albumin:creatinine ratio > 5 mg/mmol on 2wo occasions

  • Number: treatment group 1 (60); treatment group 2 (59)

  • Mean age ± SD (years): treatment group 1 (63.5 ± 9.5); treatment group 2 (64.5 ± 10.1)

  • Sex (M/F): treatment group 1 (51/9); treatment group 2 (48/11)

  • Exclusion criteria: pregnancy or potential pregnancy; urinary protein excretion > 2 g daily; SCr > 200 µmol ⁄ L; BP > 160 ⁄ 90 mm Hg at randomisation; serum cholesterol > 7 mmol/L; fasting serum TG > 6 mmol/L; hepatic transaminase > 2 x ULN; alkaline phosphatase > 1.5 ULN; HbA1c > 10% (86 mmol ⁄ mol); untreated hypothyroidism; intolerance of ARBs or statins; taking atorvastatin > 10 mg daily (or the equivalent effective dose of another statin) or use of any other lipid-lowering medication; other illness likely to influence the study

Interventions

Treatment group 1 (high dose)

  • Atorvastatin: 80 mg/d

Treatment group 2 (low dose)

  • Atorvastatin: 10 mg/d

Outcomes
  • MDRD eGFR and UAE rate

  • Lipid profile

  • CHD death

  • Non-fatal AMI

  • Hospital admission for unstable angina

  • Coronary revascularisation

  • Lower limb revascularisation or amputation or Ischaemic stroke

  • Adverse events

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAll adverse events and outcomes were assessed by an investigator who was blind to patient status
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk111/119 (93%) included in analysis of kidney function; ITT not conducted
Other biasLow riskFunding: We acknowledge support from the Manchester NIHR Biomedical Research Centre and Manchester Academic Health Sciences Centre (MAHSC). The study was funded by an unrestricted grant from Pfizer UK which markets atorvastatin. The sponsors were allowed to comment on the manuscript but they had no right of veto over any of its contents.

Panichi 2005

Methods
  • Study design: placebo-controlled RCT

  • Study duration: January to June 2004

  • Follow-up period: 6 months

Participants
  • Country: Italy

  • Setting: single centre

  • CKD and hypercholesterolaemia defined as LDL > 100 mg/dL

  • Number: treatment group (28); control group (27)

  • Mean age ± SD (years): treatment group (60 ± 10); control group (55 ± 13)

  • Sex (M/F): treatment group (23/5); control group (21/6)

  • Exclusion criteria: aged > 75 years; presence of nephrotic syndrome; DM; malignant diseases; treatment with immunosuppressant agents; connective tissue disease; any cardiovascular event in the previous 6 months; any acute disease; hypersensitivity to statins

Interventions

Treatment group

  • Simvastatin: 40 mg/d

Control group

  • Placebo

Outcomes
  • Carotid intimal thickness

  • Echo parameters

  • Lipid profile (TC, LDL, HDL, TG)

  • Kidney function

  • Inflammatory markers

  • Adverse events (creatine phosphokinase, ALT and AST)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskRandomised double-blind placebo-controlled study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskData analysers were blinded
Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant drop-outs, treatment group (8/28), control group (12/27); ITT not reported
Other biasLow riskFunding: none

PPP Study 1992

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 5 years

Participants
  • Country: international

  • Setting: multicentre

  • Three studies - CARE, LIPID, WOSCOPS studies; mild to moderate CKD (30 to 89.9 mL/min/1/.73 m²)

  • Number: 16,245

  • Mean age range: 57.5 to 63.5 years

  • Sex (M/F): 14,484/1761

  • Exclusion criteria: NR

Interventions

Treatment group

  • Pravastatin: 40 mg/d

Control group

  • Placebo

Outcomes
  • All-cause mortality

  • Cardiovascular death

  • Non-fatal MI, coronary revascularisation, non-fatal stroke

  • Lipid profile

  • Kidney function (GFR)

NotesThis is a combined analysis of three different studies conducted in the general population.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskComputer-generated allocation numbers
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskYes
Incomplete outcome data (attrition bias)
All outcomes
Low riskITT performed; analyses in this article were not prespecified in the original Pravastatin Pooling Project (PPP) protocol but were specified before examining information on kidney function and were undertaken on ITT basis
Other biasLow riskFunding: The CARE, LIPID, and WOSCOPS studies and this substudy on kidney disease are investigator-initiated studies funded by Bristol-Myers Squibb. Statistical analyses were performed at Wake Forest University, Winston-Salem, NC, independently of the sponsor. The authors had unlimited access to the data used in this analysis. The sponsor is entitled to comment on manuscripts before submission, and the authors may consider these comments, but the rights to publication reside contractually with the investigators. The sponsor maintained information on adverse events and other trial data, as required by federal regulation

PREVEND IT 2000

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 46 months

Participants
  • Country: Netherlands

  • Setting: community-based

  • Persistent microalbuminuria with lipid levels from 5 to 8 mmol/L with or without prior CVD

  • Number: treatment group (433); control group (431)

  • Mean age ± SD (years): treatment group (52.1 ± 11.9); control group (50.5 ± 11.7)

  • Sex (M/F): treatment group (290/141); control group (267/164)

  • Exclusion criteria: CrCl < 60% of the normal age adjusted value and use of ACEi or ARB

Interventions

Treatment group

  • Pravastatin: 40 mg/d

Control group

  • Placebo

Outcomes
  • Cardiovascular death

  • Non-fatal MI, coronary revascularisation, non-fatal stroke

  • Cardiovascular hospitalisation

  • Lipid profile

  • Albuminuria

  • BP

NotesSubgroup analysis of larger study conducted in general population
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation performed in blocks of 20 based on computer-generated randomisation list
Allocation concealment (selection bias)Low riskSubjects meeting the randomisation criteria were allocated to a treatment number in the order in which they entered the randomised study period
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAn independent endpoint committee reviewed all end points. Committee members had no knowledge of the subject’s treatment assignment
Incomplete outcome data (attrition bias)
All outcomes
Low risk> 10% withdrawals in treatment and control arms; all analyses were performed on ITT basis
Other biasLow riskFunding: financially supported by grant E.013 of the Dutch Kidney Foundation, grant NHS 99.103 and NHS 2002-B202 of the Netherlands Heart Foundation, and an unrestricted grant of Bristol-Myers Squibb

Rayner 1996

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 24 months

Participants
  • Country: South Africa

  • Setting: university

  • Hypertension and GFR 22 to 55 mL/min and on ACEi; fasting cholesterol > 240 mg/dL

  • Number: treatment group (12); control group (12)

  • Mean age ± SD (years): NR

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Simvastatin: 10 to 40 mg/d

  • Diet

Control group

  • None

Outcomes
  • Lipid profile

  • Albuminuria

  • Kidney function (GFR)

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskPatients were alternatively allocated to treatment and control groups
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk9/17 terminated study and were not included in analyses; ITT not performed
Other biasUnclear riskFunding: NR

Renke 2010a

Methods
  • Study design: placebo-controlled, cross-over RCT

  • Study duration: NR

  • Follow-up period: 12 weeks

Participants
  • Country: Poland

  • Setting: single centre

  • Aged 18 to 65 years, chronic non-diabetic proteinuric nephropathy without dyslipidaemia, normal or slightly impaired stable kidney function expressed as eGFR > 45 mL/min, stable proteinuria > 300 mg/24 h, and no steroids or other immunosuppressive treatment for a minimum of 6 months before the study

  • Number: 14

  • Mean age ± SD: 4.2 ± 6.9 years

  • Sex (M/F): 7/7

  • Exclusion criteria: nephrotic syndrome; DM; CVD; potassium serum level > 5.1 mmol/L; history of malignancy including leukaemia and lymphoma; fertile women who were not taking oral contraceptives; pregnant or lactating women; patients with active liver disease, i.e. AST or ALT values > 3 x ULN; known or suspected contraindications to study medications, including history of adverse reactions to statins, ACEI or ARB

Interventions

Treatment group

  • Atorvastatin: 40 mg

Control group

  • Placebo

Outcomes
  • Lipid profile

  • 24 h protein excretion

  • Urinary NAG excretion

  • eGFR

  • BP

  • Adverse events: AST, ALT, CKD levels

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random list
Allocation concealment (selection bias)Unclear riskNot adequately described
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk12/14 (86%) completed protocol; ITT not conducted
Other biasLow riskFunding: supported by grant from the Committee for Scientific Research through the Medical University
of Gdansk (ST-4 and W-80). The authors thank Pfizer Polska and Adamed for providing drugs. The drug providers and sponsors had no involvement in the study design, patient recruitment, analysis, interpretation of data, writing of the report, or the decision to submit the report for publication

Samuelsson 2002

Methods
  • Study design: placebo-controlled cross-over RCT

  • Study duration: NR

  • Follow-up period: 8 weeks

Participants
  • Country: Sweden

  • Setting: multicentre (2)

  • Non-nephrotic patients with primary CKD and moderate to advanced renal insufficiency

  • Number: 45

  • Mean age ± SD: 56.4 ± 11 years

  • Sex (M/F): 28/17

  • Exclusion criteria: secondary kidney disease (such as DM); ongoing immunosuppressive treatment; heavy proteinuria combined with hypoalbuminaemia and oedema; ongoing oestrogen therapy; ongoing lipid lowering therapy

Interventions

Treatment group

  • Fluvastatin: 40 mg

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Lipoprotien profile

  • EDTA GFR

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasHigh riskFunding: supported in part by a research grant from AstraZeneca, Molndal, Sweden, and resources of the Oklahoma Medical Research Foundation, Oklahoma City, OK, USA

Sawara 2008

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period:12 months

Participants
  • Country: Japan

  • Setting: single centre

  • CKD with eGFR < 90 mL/min and > 15 mL/min

  • Number: treatment group (11); control group (16)

  • Mean age ± SD (years): treatment group (63.8 ± 9.1); control group (67.0 ± 7.9)

  • Sex (M/F): treatment group (11/11); control group (9/7)

  • Exclusion criteria: LDL < 100 mg/dL or > 200 mg/dL, existence of liver, cardiovascular, infectious or systemic diseases

Interventions

Treatment group

  • Rosuvastatin: 2.5 mg/d

Control group

  • No lipid lowering drug

Outcomes
  • Lipid profile (TC, LDL, HDL, TG)

  • Inflammatory markers

  • Carotid intimal thickness

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High riskSignificant number of drop-outs; ITT not performed
Other biasUnclear riskFunding: NR

Scanferla 1991

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 24 months

Participants
  • Country: Italy

  • Setting: university

  • Biopsy proven IMN with SCr < 150 µmol/L; urine protein > 6.1 g/24 h; fasting cholesterol > 6.1 mmol/L

  • Number: treatment group (9); control group (8)

  • Mean age (year): treatment group (42); control group (45)

  • Sex (M/F): NR

  • Exclusion criteria: cataracts; fasting serum triglycerides > 4.5 mmol/L; liver disease; previous lipid-lowering therapy; pregnancy; contraceptives

Interventions

Treatment group

  • Simvastatin: 10 mg/d

  • Diet

Control group

  • None

Outcomes
  • Lipid profile

  • Kidney function (GFR)

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskNR

SHARP Study 2010

Methods
  • Study design: RCT

  • Study duration: August 2003 to August 2010

  • Follow-up period: 4.9 years

Participants
  • Country: International

  • Setting: multicentre

  • Men or women aged ≥40 years; predialysis (SCr ≥ 1.7 mg/dL (≥150 μmol/L) in men or ≥1.5 mg/dL (≥ 130 μmol/L) in women at both the most recent routine clinic visit and the study screening visit) or dialysis (haemodialysis or peritoneal dialysis)

  • Number: treatment group (1533); control group (1490)

  • Mean age ± SD (years): NR

  • Sex (M/F): NR

  • Exclusion criteria: definite history of MI or coronary revascularisation procedure; functioning renal transplant or living donor kidney transplant planned; < 2 months since presentation as acute uraemic emergency; definite history of chronic liver disease or abnormal liver function (i.e. ALT N1.5 x ULN or, if ALT unavailable, AST N1.5 x ULN) (patients with a history of hepatitis were eligible if these limits were not exceeded); evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis) or CK N3 x ULN; definite previous adverse reaction to a statin or to ezetimibe; concurrent treatment with a contraindicated drug: statins; ezetimibe; fibrates; nicotinic acid; cyclosporin; erythromycin, clarithromycin; imidazole or triazole antifungals such as itraconazole, ketoconazole; protease-inhibitors such as antiretroviral drugs for HIV infection; nefazodone; child-bearing potential (i.e. premenopausal women not using reliable method of contraception); known to be poorly compliant with clinic visits or prescribed medication; medical history that might limit the individual's ability to take the study treatments for the duration of the study (eg severe respiratory disease, history of cancer other than non-melanoma skin cancer, or recent history of alcohol or substance misuse)

Interventions

Treatment group

  • Simvastatin

  • Ezetimibe

Control group

  • Placebo

Outcomes
  • Major atherosclerotic events (defined as non-fatal MI or coronary death, non-haemorrhagic stroke, or arterial revascularisation excluding dialysis access procedures)

  • Lipid profile

  • Kidney function: SCr

  • Adverse events: CK, ALT or AST

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAllocated by local study laptop computer with minimised randomisation
Allocation concealment (selection bias)Low riskLocal laptop computer that was synchronised regularly with central database and double-dummy treatment to ensure blinding
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-dummy 2 x 2 factorial design
Blinding of outcome assessment (detection bias)
All outcomes
Low riskCentral adjudication by trained clinicians who were masked to study treatment allocation
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants included in analyses; ITT conducted
Other biasLow riskFunding: funded by Merck/Schering-Plough Pharmaceuticals (North Wales, PA, USA), with additional
support from the Australian National Health Medical Research Council, the British Heart Foundation, and the UK Medical Research Council. SHARP was initiated, conducted, and interpreted independently of the principal study funder

Stegmayr 2005

Methods
  • Study design: RCT

  • Study duration: from February 1998

  • Follow-up period: 5 years

Participants
  • Country: Sweden

  • Setting: multicentre

  • GFR < 30 mL/min

  • Number: treatment group (70); control group (73)

  • Mean age ± SD (years): treatment group (67.8 ± 12.4); control group (69.4 ± 10.2)

  • Sex (M/F): treatment group (48/22); control group (51/22)

  • Exclusion criteria: aged < 18 years; fertile women not taking oral contraceptives; pregnant or lactating women; active liver disease; history of adverse reactions to statins; patients with functioning kidney transplant not on dialysis; patients waiting for transplantation; those on a protein-restricted diet < 40 g of protein/d; poor compliance to medication and follow-up; history of a progressive malignancy and life expectance < 6 months

Interventions

Treatment group

  • Atorvastatin: 10 mg/d

Control group

  • Placebo

Outcomes
  • All-cause mortality

  • Acute MI, need for PTCA, CABG

  • Lipid profile

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskRandomisation was done by means of a telephone call to the study data centre where sealed envelopes were drawn
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients analysed; ITT performed
Other biasLow riskFunding: Samverkansnamnden for the Region of Northern Sweden (Project VISARENORR), the University of Umea and the Department of Medicine, Umea University Hospital

Thomas 1993

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 24 weeks

Participants
  • Country: UK

  • Setting: multicentre (3)

  • Proteinuria 1 to 3 g/d or NS > 3.5 g/d; fasting cholesterol ≥ 6.5 mmol/L after diet therapy; age 18 to 70 years

  • Number: treatment group (15); control group (15)

  • Age (years): treatment group (52); control group (49)

  • Sex (M/F): treatment group (7/8); control group (9/6)

  • Exclusion criteria: DM; hypertriglyceridaemia warranting drug therapy; ESKD; steroid-responsive minimal change disease; uncontrolled hypertension; impaired liver function or history of hepatobiliary disease; recent MI; CABG or unstable angina; women who were pregnant, nursing, or not adequately protected against pregnancy; other lipid lowering or cyclosporin therapy; carcinoma; lymphoma or amyloidosis

Interventions

Treatment group

  • Simvastatin: 40 mg

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Proteinuria

  • Apo B100

  • Inulin clearance

  • SCr

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk7/30 patients did not complete the study; ITT not reported
Other biasUnclear riskFunding: supported by a grant from Merck Sharp & Dohme, UK

TNT Study 2005

Methods
  • Study design: RCT

  • Study duration: 1998 to 2005

  • Follow-up period: 4.9 years

Participants
  • Country: multinational (14 countries)

  • Setting: multicentre

  • Men and women aged 35 to 75 years with clinically evident CHD, defined as previous MI, previous or current angina with objective evidence of atherosclerotic CHD, or history of coronary revascularisation

  • Number: treatment group 1 (1602); treatment group 2 (1505)

  • Mean age ± SD (years): treatment group 1 (65.5 ± 7.1); treatment group 2 (65.6 ± 6.9)

  • Sex (M/F): treatment group 1 (1110/590); treatment group 2 (992/513)

  • Exclusion criteria: Hypersensitivity to statins; active liver disease or hepatic dysfunction defined as ALT or AST > 1.5 x ULN; women who were pregnant or breastfeeding; nephrotic syndrome; uncontrolled DM; uncontrolled hypothyroidism; uncontrolled hypertension (as defined by the investigator) at the screening visit; MI, coronary revascularisation procedure or severe/unstable angina within 1 month of screening; any planned surgical procedure for the treatment of atherosclerosis; ejection fraction < 30%; haemodynamically important valvular disease; GI disease limiting drug absorption or partial ileal bypass; any non skin malignancy, malignant melanoma or other survival-limiting disease; unexplained creatine phosphokinase levels > 6 x ULN; concurrent therapy with long-term immunosuppressants; concurrent therapy with lipid-regulating drugs not specified as study treatment in the protocol; history of alcohol abuse; and participation in another clinical study concurrently or within 30 days before screening

Interventions

Treatment group 1

  • Atorvastatin: 80 mg

Treatment group 2

  • Atorvastatin: 10 mg

Outcomes
  • Primary endpoint: occurrence of a major cardiovascular event, defined as death from CHD, non-fatal non–procedure-related MI, resuscitation after cardiac arrest, or fatal or non-fatal stroke

  • Secondary endpoint: major coronary event (defined as death from CHD, non-fatal non–procedure-related MI, or resuscitation after cardiac arrest), a cerebrovascular event, hospitalisation for CHF, peripheral-artery disease, death from any cause, any cardiovascular event, and any coronary event

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated code
Allocation concealment (selection bias)Low riskRandomisation code was prepared by a central unit
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAn endpoint committee reviewed (blinded) all potential primary and secondary endpoints to adjudicate the endpoint designation. The committee members who performed patient endpoint review were not investigators or sub-investigators in the study
Incomplete outcome data (attrition bias)
All outcomes
Low riskLost to follow-up details were presented in the primary publication and ITT analysis was conducted; interim analyses for the TNT study began after a median 3 year follow-up
Other biasHigh riskFunding: TNT trial (NCT00327691) was funded by Pfizer Inc (New York, NY, USA).

Tokunaga 2008

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: NR

Participants
  • Country: Japan

  • Setting: NR

  • Hypertension

  • Number: treatment group (10); control group (10)

  • Mean age ± SD (years): NR

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Pitavastatin: 10 mg

Control group

  • Placebo

Outcomes
  • Albuminuria

  • Kidney function

  • Lipid profile

  • CRP

NotesAbstract only
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label study
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Tonolo 1997

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 24 months

Participants
  • Country: Italy

  • Setting: single centre

  • Normotensive type 2 DM patients in good metabolic control HbA1c < 7.5% at any time in previous year

  • Number: treatment group (10); control group (9)

  • Mean age ± SD (years): treatment group (60 ± 3); control group (62 ± 7)

  • Sex (M/F): treatment group (8/2); control group (6/3)

  • Exclusion criteria: NR

Interventions

Treatment group

  • Simvastatin: 20 mg

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Kidney function (CrCl)

  • Albumin excretion rate

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High riskDropouts NR; ITT not performed
Other biasUnclear riskFunding: NR

UK-HARP-I 2005

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 12 months

Participants
  • Country: UK

  • Setting:

  • Age > 18 years; pre-dialysis patients with SCr > 1.7 mg/dL; HD or PD patients; or kidney transplant (with any creatinine level)

  • Number: treatment group 1 (112); treatment group 2 (112); treatment group 3 (113); control group (111)

  • Mean age ± SD (years): treatment group 1 (54 ± 14); treatment group 2 (52 ± 15); treatment group 3 (52 ± 16); control group (54 ± 15)

  • Sex (M/F): treatment group 1 (78/34); treatment group 2 (79/33); treatment group 3 (81/32); control group (76/35)

  • Exclusion criteria: recent history of acute uraemia; history of chronic liver disease; inflammatory muscles disease; CK > 3 x ULN; previous adverse reaction to a statin or history of aspirin hypersensitivity; concurrent treatment with a contraindicated drug; high immediate risk for bleeding; child-bearing potential in the absence of a reliable method of contraception; a life-threatening condition other than CKD or vascular disease; frequent non-attendance at clinics or known non-compliance with drug treatments; or alcohol or substance abuse

Interventions

Treatment group 1

  • Simvastatin: 20 mg/d

  • Aspirin: 100 mg/d

Treatment group 2

  • Simvastatin: 20 mg/d

Treatment group 3

  • Aspirin: 100 mg/d

Control group

  • Double placebo

Outcomes
  • Mortality

  • Lipid profile

  • Apo A1, B

  • CrCl (mL/min) changes

  • Glomerular sclerosis and interstitial fibrosis

  • Renal fat deposits

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskMinimised randomisation used to balance the treatment groups
Allocation concealment (selection bias)Low riskRandomisation by telephone to the Clinical Trial Service Unit
Blinding of participants and personnel (performance bias)
All outcomes
Low riskMatching placebo
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskAll events were coded centrally according to a standard protocol. Otherwise unclear
Incomplete outcome data (attrition bias)
All outcomes
Low risk442/448 patients completed follow up; ITT performed
Other biasLow riskFunding: The HARP pilot studies and the Study of Heart and Renal Protection (SHARP) were funded by unrestricted grants from Merck & Co. CB, ML, JA, and RC each received reimbursement from Merck for travel expenses in connection with various speaking engagements, but as members of the Clinical Trial Service Unit, comply with the Unit’s policy of not accepting honoraria.

Verma 2005

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 20 weeks

Participants
  • Country: Georgia

  • Setting: multicentre (2)

  • Age > 18 years; CKD defined by GFR < 60 mL/min/1.73 m² BSA; no clinical evidence of AKI; not undergoing HD; not recently hospitalised for any reason; no known recent acute illness or infection; not currently taking anti-lipidaemic medications; no history of statin therapy discontinuation because of adverse events; no known contraindications to statin therapy; fasting LDL > 100 mg/dL; HDL < 40 mg/dL; TG > 150 mg/dL

  • Number: treatment group (48); control group (43)

  • Mean age ± SD (years): treatment group (73 ± 10); control group (74 ± 19)

  • Sex (M/F): treatment group (19/29); control group (13/30)

  • Exclusion criteria: NR

Interventions

Treatment group

  • Rosuvastatin" 10 mg

Control group

  • No treatment

Outcomes
  • Lipid profile

  • Kidney function (CrCl, SCr)

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
High risk7/91 were excluded; ITT not performed
Other biasUnclear riskFunding: NR

Yasuda 2004

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 48 weeks

Participants
  • Country: Japan

  • Setting: university

  • Non-insulin dependent diabetic nephropathy and patients with GN

  • Number: treatment group (39); control group (41)

  • Mean age ± SD (years): treatment group (57 ± 2); control group (58 ± 2)

  • Sex (M/F): treatment group (18/21); control group (19/22)

  • Exclusion criteria: NR

Interventions

Treatment group

  • Fluvastatin: 20 mg

Control group

  • Diet

Outcomes
  • Lipid profile

  • Kidney function (CrCl, SCr)

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
High risk8/88 patients excluded from the study; ITT not performed
Other biasUnclear riskFunding: NR

Zhang 1995

  1. a

    ADPKD - autosomal dominant polycystic kidney disease; ACEi - angiotensin-converting enzyme inhibitors; AKI - acute kidney injury; ALT - alanine aminotransferase; AMI - acute myocardial infarction; Apo - apolipoprotein; ARB - angiotensin receptor blockers; AST - aspartate aminotransferase; BP - blood pressure; BSA - body surface area; CABG - coronary artery bypass graft; CHD - congestive heart disease; CHF - congestive heart failure; CKD - chronic kidney disease; CrCl - creatinine clearance; CRP - C-reactive protein; CV - cardiovascular; CVA - cardiovascular accident; ECG - electrocardiograph; eGFR - estimated glomerular filtration rate; GN - glomerulonephritis; DBP - diastolic blood pressure; ESKD - end-stage kidney disease; FSGS - focal segmental glomerulosclerosis; GFR - glomerular filtration rate; GN - glomerulonephritis; HbA1c - glycated haemoglobin; HDL - high-density lipoprotein; IgA - immunoglobulin A; IMN - idiopathic membranous nephropathy; ITT - intention-to-treat; LDL - low-density lipoprotein; MDRD - modification of diet in renal disease; MI - myocardial infarction; MPGN - membranoproliferative glomerulonephritis; NR - not reported; NSAID - nonsteroidal anti-inflammatory drug; NYHA - New York Heart Association; PTCA - percutaneous transluminal coronary angiography; RRT - renal replacement therapy; SBP - systolic blood pressure; SCr - serum creatinine; TC - total cholesterol; TG - triglycerides; TIA - transient ischaemic attack; TSH - thyroid-stimulating hormones; UAE - urinary albumin excretion; ULN - upper limit of normal; UTI - urinary tract infection

Methods
  • Study design: RCT

  • Study duration: NR

  • Follow-up period: 24 weeks

Participants
  • Country: Belgium

  • Setting: single centre

  • Insulin dependent DM and persistent microalbuminuria (20 to 200 µg/min)

  • Number: treatment group (10); control group (10)

  • Mean age ± SD (years): NR

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Pravastatin: 20 mg/d

Control group

  • Placebo

Outcomes
  • Lipid profile

  • Apo A1, Apo B

  • Urinary albumin

  • Metabolic control (blood glucose, HbA1c)

NotesDedicated CKD study
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear riskNR
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label
Blinding of outcome assessment (detection bias)
All outcomes
High riskOpen-label
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Other biasUnclear riskFunding: NR

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    CKD - chronic kidney disease; RCT - randomised controlled trial

ALLHAT & ALHAT-LLT 1996Wrong intervention
ATIC Study 2005Wrong intervention
AURORA Study 2005Wrong population (not predialysis)
Dalla Nora 2003Wrong population (not CKD)
David 2008Wrong intervention
Deighan 2001Wrong intervention
Dogra 2005Short duration
Dogra 2007Short duration
Dyadyk 2006Not RCT
Garcia-de-la-Puente 2009Wrong population (paediatric)
Golper 1987Duration not reported
Golper 1989Short duration
Kano 2003Wrong population and intervention (paediatric)
Kostapanos 2007Wrong population (not CKD)
Mackie 2010Wrong population (paediatric)
MASTERPLAN Study 2005Wrong intervention (not statin)
Nakamura 2001cNot RCT
Nakamura 2010aWrong intervention
Ott 2008Short duration
Paniagua 2002Wrong population (not CKD)
Paulsen 2010Short duration
Rammos 2005Not randomised
Samuelsson 1997Wrong intervention
Schmieder 2003Short duration
STENO-2 Study 1999Wrong intervention
Tokunaga 2004Wrong intervention
Tonolo 2006Wrong intervention
Torraca 2006Short duration
UK-HARP-II 2006Wrong intervention
Van Dijk 2001Short duration
Yasuda 2010Active intervention
Yigit 2004Not RCT

Characteristics of ongoing studies [ordered by study ID]

JPRN-UMIN000002526

Trial name or titleEffects of statin on renal function in patients with chronic kidney disease
MethodsInterventional parallel-group, randomised
Participants
  • CKD

  • Patients ≤ 120 mg/dL > LDL-C 100 mg/dL

  • Outpatients

InterventionsPitavastatin is administrated and dosage will be increased or decreased appropriately to reach the target LDL-C level (100 mg/dL)
Outcomes

Primary

  • Per cent changes in eGFR from baseline urinary protein excretion

Secondary

  • Per cent changes in TC, LDL, HDL, TG

  • Per cent changes in glucose, HbA1c

  • Per cent changes in hs-CRP

  • Per cent changes in Pentosidine, L-FABP

  • Ambulatory BP monitoring, PWV, ABI, central blood pressure

Starting date1/9/2009
Contact informationKouichi TAMURA, tamukou@med.yokohama-cu.ac.jp
Notes 

NCT00680017

Trial name or title30 week study of the combination of ABT-335 and rosuvastatin compared to rosuvastatin monotherapy for subjects with dyslipidemia and stage 3 chronic kidney disease
MethodsRandomised, parallel-group, double-blind
ParticipantsDyslipidemic subjects with CKD stage 3
Interventions

Treatment group 1

  • ABT-335 plus rosuvastatin

    • ABT-335 45 mg plus rosuvastatin 5 mg for 8 weeks

    • ABT-335 45 mg plus rosuvastatin 10 mg for 8 weeks

Treatment group 2

  • Rosuvastatin

    • Rosuvastatin 5 mg for 8 weeks

    • Rosuvastatin 10 mg for 8 weeks

Outcomes
  • Rate of change of TG

  • Rate of change of HDL

Starting dateJune 2008
Contact informationMaureen Kelly Abbott
NotesThis study has been completed

NCT00768638

Trial name or titleStudy of atorvastatin dose dependent reduction of proteinuria (SARP)
MethodsRandomised, parallel-group, double-blind
Participants

Inclusion criteria

  • Aged ≥ 18 years

  • Stage 3 or 4 CKD (modified MDRD)

  • Proteinuria > 1 g/d on ACEi or ARB or both, or proteinuria > 1 g/d with intolerance or contraindication to ACEi or ARB or both

  • BP < 130/80 mm Hg or < 140/90 mm Hg in patients with ≥ 3 antihypertensive drugs

  • Stable kidney function

Interventions

Treatment group 1

  • Atorvastatin: 40 mg

Treatment group 2

  • Atorvastatin: 10 mg

OutcomesProteinuria at 6 months
Starting dateOctober 2008
Contact informationMohsen Agharazii, MD 418-525-4444 ext 15585 mohsen.agharazii@crhdq.ulaval.ca; Contact: Johanne Blouin, SC 418-525-4444 ext 16487 johanne.blouin@chuq.qc.ca
Notes 

NCT01208701

Trial name or titleThe effects of atorvastatin on the nitrogen oxide-system in patients with type 2 diabetes and nephropathy (STAD)
MethodsRandomised, parallel-group, double-blind
Participants

Inclusion criteria

  • Men and women

  • Minimum age 40 years

  • CKD

  • eGFR 30 to 90 mL/min

  • Type 2 DM

Exclusion criteria

  • Nephrotic syndrome

  • Anamnestic or clinical signs of significant heart, lung, lever, kidney and brain disease

  • Neoplastic disease

  • Alcohol abuse

  • Drug abuse

  • Pregnancy or nursing

  • Blood donation within a month before examination

  • Hb < 6.0

Interventions

Treatment group

  • Atorvastatin: 80 mg/d for 5 days

Control group

  • Placebo

Outcomes

Primary outcome

  • Fractional excretion of sodium (5 days treatment)

Secondary outcome measures (Study duration 5 days)

  • Systolic BP

  • Plasma renin concentration

  • Arterial stiffness

  • Plasma angiotensin II concentration

  • Urinary excretion of protein from sodium channels such as the NaCl co transporter (NCC), the Na-K-Cl co transporter (NKCC) and the epithelial sodium channel (ENaC)

  • Augmentations index

Starting dateMay 2010
Contact information

Frank H Christensen, MD + 45 99125429 frank.holden.christensen@vest.rm.dk

Thomas Larsen, MD + 45 9912 5425 thomalse@rm.dk

Notes 

NCT01213498

Trial name or titleThe effects of atorvastatin on the nitric oxide-system in patients With non-diabetic nephropathy (STAN)
MethodsRandomised, parallel-group, double-blind
Participants

Inclusion criteria

  • Men and women

  • Minimum age 20 years

  • CKD

  • eGFR from 30 to 90 mL/min

Exclusion criteria

  • Nephrotic syndrome

  • DM

  • Anamnestic or clinical signs of significant heart, lung, lever, kidney, thyroid and brain disease

  • Neoplastic disease

  • Alcohol abuse

  • Drug abuse

  • Pregnancy or nursing

  • Blood donation within a month before examination

  • Hb < 6.0

Interventions

Treatment group

  • Atorvastatin: 80 mg/d for 5 days

Control group

  • Placebo

Outcomes

Primary outcomes

  • Fractional excretion of sodium (FeNa) (5 days treatment)

  • Fractional excretion of urinary sodium before, during and after L-NMMA infusion

Secondary outcome measures (Study duration: 5 days):

  • Systolic BP

  • Plasma renin concentration

  • Arterial stiffness (pulse wave velocity)

  • DBP

  • Augmentation Index

  • UAE

  • Urinary excretion of protein from sodium channels such as the NaCl co-transporter (NCC), the Na-K-Cl co-transporter (NKCC) and the epithelial sodium channel (ENaC)

  • Plasma aldosterone concentration

  • Urinary Aquaporin 2 (u-AQP2) excretion

  • Atrial natriuretic peptide (ANP) concentration

  • Brain natriuretic peptide concentration

Starting dateMay 2010
Contact information

Frank H Christensen, MD +45 99125429 frank.holden.christensen@vest.rm.dk

Thomas Larsen, MD +45 9912 5425 thomalse@rm.dk

Notes 

PLANET I Study 2006

Trial name or titleProspective evaluation of proteinuria and renal function in diabetic patients With progressive renal disease (PLANET 1)
MethodsRandomised, double-blind, 52 week, parallel group, multicentre phase IIb study
ParticipantsHypercholesterolaemic diabetic patients with moderate proteinuria
Interventions

Treatment group 1

  • Rosuvastatin: 10 mg

Treatment group 2

  • Rosuvastatin: 40 mg

Treatment group 3

  • Rosuvastatin: 80 mg

OutcomesUrinary protein to creatinine ratio at weeks 26 and 52
Starting dateFebruary 2006
Contact informationAstra Zeneca Crestor Medical Science Director
Notes 

PLANET II Study 2006

Trial name or titleProspective evaluation of proteinuria and renal function in non-diabetic patients with progressive renal disease (PLANET II)
MethodsRandomised, double-blind, 52 week, parallel group, multicentre phase IIb study
ParticipantsHypercholesterolaemic diabetic patients with moderate proteinuria
Interventions

Treatment group 1

  • Rosuvastatin

Treatment group 2

  • Atorvastatin

OutcomesUrinary protein to creatinine ratio at weeks 26 and 52
Starting dateFebruary 2006
Contact informationAstra Zeneca Crestor Medical Science Director
Notes 

VICTORY Study 2009

  1. a

    ACEi - angiotensin-converting enzyme inhibitors; ALT - alanine aminotransferase; ARB - angiotensin receptor blockers; BP - blood pressure; CKD - chronic kidney disease; CRP - C-reactive protein; eGFR - estimated glomerular filtration rate; DBP - diastolic blood pressure; HbA1c - glycated haemoglobin; HDL - high-density lipoprotein; LDL - low-density lipoprotein; MDRD - modification of diet in renal disease; NYHA - New York Heart Association; SBP - systolic blood pressure; TC - total cholesterol; TG - triglycerides; UAE - urinary albumin excretion; UTI - urinary tract infection

Trial name or titleEzetimibe/simvastatin combination in proteinuric nephropathy (VICTORY)
MethodsParallel-group, randomised, open-label
Participants

Inclusion criteria

  • Aged > 18 years

  • LDL > 100 mg/dL (without concomitant hypolipidaemic drugs) in patients with high cardiovascular risk for the concomitant presence of:

    • proteinuric chronic nephropathy defined as CrCl > 20 mL/min/1.73 m² combined with a urinary protein excretion rate > 0.3 g/24h, without evidence of UTI or overt heart failure (NYHA class III or more)

    • hypertension defined as a SBP or BBP > 140 or 90 mm Hg respectively (or less in patients with concomitant antihypertensive therapy)

Exclusion criteria

  • Previous or concomitant treatment with steroids, anti-inflammatory and immunosuppressive agents

  • Evidence or suspicion of renovascular disease, obstructive uropathy, type I diabetes mellitus, vasculitides, history of poor tolerance or allergy to ACEi and ATA, statin or EZE, drug abuse or pregnancy

  • Inability to fully understand the purposes/risks of the study and to provide a written informed consent

Interventions

Treatment group 1

  • Ezetimibe/simvastatin combined therapy at the dose of 10/20 mg/d

Treatment group 2

  • Ezetimibe/simvastatin combined therapy at the dose of 10/40 mg/day

Treatment group 3

  • Simvastatin: 40 mg/d

Outcomes

Primary outcome

  • To assess whether EZE-statin combined therapy is more effective than statin alone to achieve the optimum lipid control (LDL < 70 mg/dL) in chronic proteinuric nephropathy

Secondary outcomes

  • To assess the effect of EZE-statin combined therapy versus statin monotherapy on other outcome variables including:

    • renal parameters

    • inflammatory status

    • markers of endothelial dysfunction

Starting dateNovember 2008
Contact informationIstituto di Patologia Medica - Azienda Ospedaliero Universitaria, Sassari, Italy, 07100
Notes