HMG CoA reductase inhibitors (statins) for dialysis patients

  • Conclusions changed
  • Review
  • Intervention

Authors

  • Suetonia C Palmer,

    1. University of Otago Christchurch, Department of Medicine, Christchurch, New Zealand
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  • Sankar D Navaneethan,

    1. Glickman Urological and Kidney Institute, Cleveland Clinic, Department of Nephrology and Hypertension, Cleveland, OH, USA
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  • 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
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  • David W Johnson,

    1. Princess Alexandra Hospital, Department of Nephrology, Woolloongabba, Queensland, Australia
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  • Vlado Perkovic,

    1. The George Institute for Global Health, Renal and Metabolic Division, Camperdown, NSW, Australia
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  • Sagar U Nigwekar,

    1. Harvard Medical School, Brigham and Women's Hospital, Massachusetts General Hospital, Scholars in Clinical Sciences Program, Boston, MA, USA
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  • Jorgen Hegbrant,

    1. Diaverum Renal Services Group, Medical Office, Lund, Sweden
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  • 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
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Abstract

Background

People with advanced kidney disease treated with dialysis experience mortality rates from cardiovascular disease that are substantially higher than for the general population. Studies that have assessed the benefits of statins (HMG CoA reductase inhibitors) report conflicting conclusions for people on dialysis and existing meta-analyses have not had sufficient power to determine whether the effects of statins vary with severity of kidney disease. Recently, additional data for the effects of statins in dialysis patients have become available. This is an update of a review first published in 2004 and last updated in 2009.

Objectives

To assess the benefits and harms of statin use in adults who require dialysis (haemodialysis or peritoneal dialysis).

Search methods

We searched the Cochrane Renal Group's Specialised Register to 29 February 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 and treatment-related toxicity in adults treated with dialysis were sought for inclusion.

Data collection and analysis

Two or more authors independently extracted data and assessed study risk of bias. Treatment effects were summarised using a random-effects model and subgroup analyses were conducted to explore sources of heterogeneity. Treatment effects were expressed as mean difference (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI).

Main results

The risk of bias was high in many of the included studies. Random sequence generation and allocation concealment was reported in three (12%) and four studies (16%), respectively. Participants and personnel were blinded in 13 studies (52%), and outcome assessors were blinded in five studies (20%). Complete outcome reporting occurred in nine studies (36%). Adverse events were only reported in nine studies (36%); 11 studies (44%) reported industry funding.

We included 25 studies (8289 participants) in this latest update; 23 studies (24 comparisons, 8166 participants) compared statins with placebo or no treatment, and two studies (123 participants) compared statins directly with one or more other statins. Statins had little or no effect on major cardiovascular events (4 studies, 7084 participants: RR 0.95, 95% CI 0.88 to 1.03), all-cause mortality (13 studies, 4705 participants: RR 0.96, 95% CI 0.90 to 1.02), cardiovascular mortality (13 studies, 4627 participants: RR 0.94, 95% CI 0.84 to 1.06) and myocardial infarction (3 studies, 4047 participants: RR 0.87, 95% CI 0.71 to 1.07); and uncertain effects on stroke (2 studies, 4018 participants: RR 1.29, 95% CI 0.96 to 1.72).

Risks of adverse events from statin therapy were uncertain; these included effects on elevated creatine kinase (5 studies, 3067 participants: RR 1.25, 95% CI 0.55 to 2.83) or liver function enzymes (4 studies, 3044 participants; RR 1.09, 95% CI 0.41 to 1.25), withdrawal due to adverse events (9 studies, 1832 participants: RR 1.04, 95% CI 0.87 to 1.25) or cancer (2 studies, 4012 participants: RR 0.90, 95% CI 0.72 to 1.11). Statins reduced total serum cholesterol (14 studies, 1803 participants; MD -44.86 mg/dL, 95% CI -55.19 to -34.53) and low-density lipoprotein cholesterol (12 studies, 1747 participants: MD -39.99 mg/dL, 95% CI -52.46 to -27.52) levels. Data comparing statin therapy directly with another statin were sparse.

Authors' conclusions

Statins have little or no beneficial effects on mortality or cardiovascular events and uncertain adverse effects in adults treated with dialysis despite clinically relevant reductions in serum cholesterol levels.

摘要

羥甲基戊二醯輔酶A(HMG CoA)還原酶抑制劑(statins)用於透析病人

背景

需接受透析治療的嚴重腎臟病病人心血管疾病死亡率高於一般人。研究指出statins (HMG CoA還原酶抑制劑)對透析病人的好處仍有爭議,統合分析也未證實statins對不同程度腎臟病是否有好處。近來有關statins用於透析病人的結果數據已經發表。本篇回顧第一次發表是在2004年,最近一次更新是在2009年。

目的

評估statins用於成人血液或腹膜透析治療之效益和風險。

搜尋策略

我們透過搜尋與本篇回顧相關的字彙與研究試驗專員連繫,搜尋考科藍腎臟群組專業註冊 (Cochrane Renal Group's Specialised Register) (截至2012年2月29日為止)。

選擇標準

我們納入隨機對照試驗和類隨機對照試驗,比較介入組(statins)和對照組(安慰劑或未接受治療或標準治療或其他statins)對成人透析治療之死亡率、心血管事件、治療相關毒性。

資料收集與分析

兩位(含)以上作者獨立擷取數據並評估研究風險偏差。以隨機效應模組分析治療作用,執行次群組分析評估異質性來源。連續性變項終點以平均值差呈現,二分變項終點以風險比和95%信賴區間呈現。

主要結果

所納入之研究多數屬高風險性偏差。隨機順序產生偏差有3篇(占12%),分派隱匿偏差有4篇(占16%)。有13篇(占52%)研究對受試者和研究人員採行盲法,有5篇研究(占20%)對受試者和研究人員及資料分析人員採行盲法。有9篇研究(占36%)有完整報告資料。有9篇研究(占36%)有報導不良事件。有11篇研究(占44%)由業界資助。

本篇回顧我們共納入25篇研究(8289位受試者),有23篇研究(8166位受試者)是比較statin和安慰劑或未接受治療之間的作用,有2篇研究(123位受試者)是直接比較不同statins之間的作用。有4篇研究(7084位受試者)結果顯示statins對降低主要心血管事件未達統計顯著差異(RR 0.95, 95% CI 0.88 to 1.03),有13篇研究(4705位受試者)結果顯示statins對降低全因死亡率未達統計顯著差異(RR 0.96, 95% CI 0.90 to 1.02),有13篇研究(4627位受試者)結果顯示statins對降低心血管死亡率未達統計顯著差異(RR 0.94, 95% CI 0.84 to 1.06),有3篇研究(4047位受試者)結果顯示statins對降低心肌梗塞事件未達統計顯著差異(RR 0.87, 95% CI 0.71 to 1.07),有2篇研究(4018位受試者)結果顯示statins對降低中風事件未達統計顯著差異(RR 1.29, 95% CI 0.96 to 1.72)。

接受statin治療發生不良事件之風險未知,這些不良事件包括如下:有5篇研究(3067位受試者)結果顯示肌酸激酶上升( RR 1.25, 95% CI 0.55 to 2.83),有4篇研究(3044位受試者)結果顯示肝功能酵素上升(RR 1.09, 95% CI 0.41 to 1.25),有9篇研究(1832位受試者)結果顯示因不良事件而退出試驗(RR 1.04, 95% CI 0.87 to 1.25),有2篇研究(4012位受試者)結果顯示罹癌(RR 0.90, 95% CI 0.72 to 1.11)。有14篇研究(1803位受試者)結果顯示statins可以降低血中總膽固醇濃度(MD -44.86 mg/dL, 95% CI -55.19 to -34.53),有12篇研究(1747位受試者)結果顯示statins可以降低低密度脂蛋白膽固醇濃度(MD -39.99 mg/dL, 95% CI -52.46 to -27.52)。不同statins之間直接比較的數據稀疏。

作者結論

雖然statins可以降低血中膽固醇濃度,但是statins對接受透析治療之成人的死亡率或心血管事件只有些許作用甚或沒有作用,而且具有不確定性的不良事件。

譯註

翻譯者:江吉文(Chi-Wen Chiang)
服務單位:屏東醫院,藥劑科(Department of Pharmacy, Pingtung Hospital, MOHW)
職稱:藥師;RPh, CDE, PhD, Assistant Professor

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Plain language summary

Does statin therapy improve survival or reduce risk of heart disease in people on dialysis?

Adults with severe kidney disease who are treated with dialysis have high risks of developing heart disease. Statin treatment reduces risks of death and complications of heart disease in the general population.

In 2009 we identified 14 studies, enrolling 2086 patients, and found that while statins were generally safe and reduced cholesterol levels, they did not prevent death or clinical cardiac events in people treated with dialysis. This latest update analysed a total or 25 studies (8289 patients), and included the results from two new large studies. We found that statins lowered cholesterol in people treated with dialysis but did not prevent death, heart attack, or stroke.

Evidence for side-effects was incomplete, and potential harms from statin therapy remain uncertain. Current study data did not address whether statin treatment should be stopped when a person starts dialysis, although the benefits associated with continued treatment are likely to be small. Limited information was available for people treated with peritoneal dialysis, suggesting that more research is needed in this setting.

淺顯易懂的口語結論

透析病人接受statin治療是否可以改善存活率或降低心臟病風險?

需接受透析治療之嚴重腎病成人發生心臟病的風險較高。一般人接受statin治療可以降低死亡風險和心臟病併發症。

2009年我們納入14篇研究共2086位受試者,研究發現透析病人接受statin治療是安全的而且可以降低膽固醇濃度,但是無法預防死亡或心臟事件。本次最新回顧我們共納入25篇研究(8289位受試者),且納入2篇新的大型研究結果。我們發現statins可以降低透析病人膽固醇濃度,但是無法預防死亡、心臟病或中風。

Statins治療副作用證據不全,且潛在性傷害不確定。雖然規律服用statin有一些好處,但是目前研究數據無法告訴透析病人是否應該停用statin。接受腹膜透析病人相關訊息有限,建議未來在這方面應該要有更多的研究。

譯註

翻譯者:江吉文(Chi-Wen Chiang)
服務單位:屏東醫院,藥劑科(Department of Pharmacy, Pingtung Hospital, MOHW)
職稱:藥師;RPh, CDE, PhD, Assistant Professor

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

Laienverständliche Zusammenfassung

Verbessert die Statin-Therapie das Überleben oder vermindert sie das Risiko von Herzkrankheiten bei Menschen an der Dialyse?

Erwachsene mit schweren Nierenerkrankungen, die mit Dialyse behandelt werden, haben ein hohes Risiko für Herzkrankheiten. Statin-Behandlung reduziert das Sterberisiko und die Komplikationen von Herzkrankheiten in der allgemeinen Bevölkerung.

Im Jahr 2009 identifizierten wir 14 Studien, die 2086 Patienten einschlossen, und stellten fest, dass während Statine im Allgemeinen verträglich waren und den Cholesterinspiegel senkten, sie nicht Tod oder klinische Vorfälle die das Herz betreffen bei Patienten, die an der Dialyse sind, verhindern. Diese neueste Aktualisierung analysiert die Gesamtzahl von 25 Studien (8289 Patienten) und enthält die Ergebnisse von zwei neuen großen Studien. Wir haben festgestellt, dass Statine das Cholesterin bei Patienten, die mit Dialyse behandelt werden senken, aber nicht Tod, Herzinfarkt oder Schlaganfall verhindern.

Die Evidenz für Nebenwirkungen war unvollständig, und mögliche Schäden von der Statin-Therapie bleiben ungewiss. Aktuelle Studiendaten befassten sich nicht damit, ob die Statin-Behandlung beendet werden sollte, wenn eine Person mit der Dialyse beginnt, obwohl die Vorteile, die mit einer kontinuierlichen Behandlung verbunden sind, wahrscheinlich gering sind. Über Menschen, die mit Peritonealdialyse behandelt wurden, waren nur eingeschränkte Informationen vorhanden, was darauf hindeutet, dass mehr Forschung in diesem Setting gebraucht wird.

Anmerkungen zur Übersetzung

K. Kunzweiler, Koordination durch Cochrane Schweiz.

Резюме на простом языке

Улучшает ли терапия статинами выживание или уменьшает ли риск сердечно-сосудистых заболеваний у людей, находящихся на диализе?

Взрослые с тяжелой формой заболевания почек, которые лечатся диализом, имеют высокий риск развития сердечно-сосудистых заболеваний. Лечение статинами снижает риск смерти и осложнений сердечно-сосудистых заболеваний в общей популяции.

В 2009 году мы определили 14 исследований, включивших в общей сложности 2086 пациентов, и обнаружили, что, в то время как статины были в целом безопасны и снижали уровни холестерина, они не предотвращали смерти или клинические сердечные события у людей, находящихся на диализе. В этом последнем обновлении обзора мы проанализировали в общей сложности 25 исследований (8289 пациентов), и включали результаты двух новых крупных исследований. Мы обнаружили, что статины снизили уровень холестерина у людей, получавших диализ, но не уменьшили частоту смертей, сердечных приступов или инсультов.

Доказательства побочных эффектов были неполными, и потенциальный вред от терапии статинами остаётся неопределенным. Во включенных исследованиях не обращались к вопросу, следует ли остановить лечение статинами, когда человек начинает получать диализ, хотя польза, связанная с продолжением лечения, вероятно, будет мала. В отношении людей, получавших перитонеальный диализ, была доступна только ограниченная информация, что позволяет предполагать, что необходимы дальнейшие исследования в этой области.

Заметки по переводу

Перевод: Низамова Чулпан Ильдаровна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: lezign@gmail.com

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. Absolute approximate events rates of outcomes per year were derived from previously 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 (Herzog 1998; Trivedi 2009; Weiner 2006; Wetmore 2009)

Statin versus placebo or no treatment for dialysis patients

Patient or population: adults with chronic kidney disease

Settings: dialysis

Intervention: statin therapy

Comparison: placebo or no treatment

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Assumed risk/year/1000 treatedCorresponding risk/year/1000 treated
Placebo or no treatmentStatin
Major cardiovascular events 150 per 1000 143 per 1000 (7 fewer)
(132 to 155) (18 fewer to 5 more)
RR 0.95 (0.88 to 1.03)7804 (4)⊕⊕⊕⊕
high
All-cause mortality 200 per 1000 192 per 1000 (8 fewer)
(176 to 208) (24 fewer to 8 more)
RR 0.96 (0.90 to 1.02)4705 (13)

⊕⊕⊕

moderate

Cardiovascular mortality 100 per 1000 94 per 1000 (6 fewer)
(82 to 105) (18 fewer to 5 more)
RR 0.94 (0.84 to 1.06)4627 (13)⊕⊕⊕
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

Although cardiovascular mortality is decreasing, events among dialysis patients remains 20- to 30-times higher than for the general population (Foley 2007; Herzog 2011; USRDS 2011). Elevated circulating lipid levels is one of several factors, that also include hypertension, diabetes, and smoking, that have been implicated in the increased cardiovascular risk associated with chronic kidney disease (CKD) (Ganesh 2001; Jungers 1997; Mallamaci 2002).

How the intervention might work

Clinical studies conducted in the general population, and in people with established cardiovascular disease, have found a strong, consistent and independent association between lipid lowering, primarily low-density lipoprotein (LDL) cholesterol, and the risk of all-cause and cardiovascular mortality (Law 1994; Rossouw 1990). A linear proportional reduction in the risk of major vascular events equal to approximately 20% per 1 mmol/L (39 mg/dL) reduction in LDL cholesterol has been reported (Baigent 2005). Optimal lowering of serum lipid levels has been anticipated to lower cardiovascular and overall mortality for people treated with dialysis.

Why it is important to do this review

Study data for the benefits of lipid lowering in people on dialysis are increasingly conflicted. Our previous review (Navaneethan 2009a) identified little or no benefit from statin therapy on mortality, although one study reported fewer major cardiovascular events in people with diabetes on dialysis (4D Study 2004). The Study for Heart and Renal Protection (SHARP Study 2010, completed since our last review update), which included 3023 people on dialysis, reported that benefits for lipid-lowering therapy extended to people with advanced kidney disease on dialysis, whereas the AURORA Study 2005 (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) conducted with 2776 adults on haemodialysis, found no clear benefit for statin therapy in this population. An advisory committee to the US Food and Drug Administration that considered SHARP Study 2010 study data did not recommend lipid-lowering using simvastatin/ezetimibe in people on dialysis, citing insufficient evidence (FDA 2011).

In light of conflicting information on the benefits of statin therapy to inform clinical practice and policy in people on dialysis, together with new study data, we conducted an update of our earlier review (Navaneethan 2009a) to evaluate the benefits and harms of statin therapy in people on dialysis.

Objectives

To evaluate the benefits (reductions in all-cause mortality, cardiovascular mortality, major cardiovascular events, myocardial infarction and stroke) and harms (liver or muscle damage, or cancer) of statins compared with placebo, no treatment, or another statin in adults who require dialysis.

Methods

Criteria for considering studies for this review

Types of studies

All randomised controlled trials (RCT) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable method) of at least 8 weeks' duration that evaluated the benefits and harms of statins in adults treated with haemodialysis or peritoneal dialysis were included. The first periods of randomised cross-over studies were also included. Studies of fewer than eight weeks' duration were excluded because they were unlikely to enable detection of mortality or cardiovascular outcomes related to statin therapy (Briel 2006).

Types of participants

Inclusion criteria

Adults treated with dialysis (haemodialysis and peritoneal dialysis) irrespective of pre-existing cardiovascular disease or statin therapy were included.

Exclusion criteria

Studies in children were excluded. Studies including adults with CKD not treated with dialysis and recipients of a kidney transplant are the subject of other related reviews (Navaneethan 2009b; Navaneethan 2009c; updates in press (Palmer 2013a; Palmer 2013b)).

Types of interventions

We included studies that compared statins with placebo, no treatment or standard care, or another statin. We excluded studies that compared a statin 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 myocardial infarction

  5. Fatal and non-fatal stroke

  6. Adverse events attributable to interventions

    1. Elevated creatine kinase

    2. Elevated liver function enzymes

    3. Withdrawal due to adverse events

    4. Cancer.

Secondary outcomes

Lipid parameters (mg/dL)

  1. Serum lipid levels

    1. Total cholesterol

    2. LDL cholesterol

    3. Triglycerides

    4. High-density lipoprotein (HDL) cholesterol

Search methods for identification of studies

Electronic searches

2013 update

We searched the Cochrane Renal Group's Specialised Register to 29 February 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 relevant clinical practice guidelines, review articles and studies.

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

Data collection and analysis

Selection of studies

Two authors independently screened all abstracts retrieved by electronic searches to identify potentially relevant citations for detailed study in full text format. Studies that might have included relevant data or information on studies involving HMG Co-A reductase inhibitors were retained initially. Studies published in non-English language journals were translated before assessment for inclusion.

Data extraction and management

Two authors independently extracted data from the eligible studies using standard data extraction forms. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was included. Any further information required from the original author was requested and any relevant information obtained was included in the review. Disagreements were resolved in consultation with a third author.

Data entry was carried out by the same two authors. Treatment effects were summarised using the random-effects model but the fixed effects model was also analysed to ensure robustness of the model chosen and susceptibility to outliers. For dichotomous outcomes (cardiovascular events, mortality, and adverse events) treatment effects were summarised as relative risk (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used (lipid parameters), treatment effects were summarised using the mean difference (MD).

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

Dichotomous outcomes (e.g. fatal and non-fatal heart attack and stroke) were expressed as risk ratios (RR) with 95% confidence intervals (CI). Risk differences (RD) with 95% confidence intervals were calculated for adverse effects. Continuous outcomes were calculated as mean differences (MD) with 95% CI.

Dealing with missing data

Where applicable, study authors were contacted for further information or missing data. Data obtained in this manner were included in our analyses.

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

This update included all studies identified in the Cochrane Renal Group's Specialised Register, which is updated regularly with published and unpublished reports identified in congress proceedings. This reduces the risk of publication bias. All reports of a single study were reviewed to ensure that all outcomes were reported to reduce the risk of selection bias.

Data synthesis

We summarised evidence quality together with absolute treatment effects for mortality and cardiovascular events based on estimated baseline risks using Grading of Recommendations Assessment Development and Evaluation (GRADE) guidelines (Summary of findings for the main comparison; Guyatt 2008). Absolute numbers of people on dialysis with cardiovascular events or adverse events avoided or incurred were estimated using the risk estimate for the outcome (and associated 95% confidence interval) obtained from the corresponding meta-analysis together with the absolute population risk estimated from previously published observational studies (Herzog 1998; Trivedi 2009; Weiner 2006; Wetmore 2009).

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 participant type, intervention, or study-related characteristics, when subgroups contained four or more independent studies: dialysis type (peritoneal or haemodialysis); statin type; statin dose (equivalent to simvastatin); baseline cholesterol (< 230 mg/dL versus ≥ 230 mg/dL); age (≤ 55 years versus > 56 years); proportion with diabetes (> 20% versus < 20%); adequacy of allocation concealment. Insufficient numbers of studies reporting one or more events were available to explore for publication bias using visual inspection of an inverted funnel plot or formal statistical analysis.

Sensitivity analysis

Where a study's results differed considerably from other studies in a meta-analysis, exclusion of the study was investigated to determine whether this altered the result of the meta-analysis.

Results

Description of studies

Results of the search

Initial review (2004) and first update (2009)

The searches identified 88 reports in 2004 and 115 reports in 2009. After title and abstract screening 67 (2004) and 97 (2009) reports were excluded. Full text assessment resulted in six studies (7 reports, 357 participants) included in our initial 2004 review and 14 studies (32 reports, 2086 participants) included in the 2009 update. Two studies reported as ongoing in 2004 and 2009 (AURORA Study 2005; SHARP Study 2010) have been included in our 2013 update.

2013 review update

Electronic searching to February 2012 identified 71 additional records. Of these, 33 were duplicate reports of existing studies and four were ongoing studies. After full-text assessment, a study by Joy 2008 included in our 2009 review update was considered to be a part of Dornbrook-Lavender 2005. We also removed Fiorini 1994 because it did not evaluate a statin versus another statin, placebo, or no treatment; and Dogra 2007, because treatment duration was only six weeks. This meant that 11 unique studies were retained from the 2009 published review (Navaneethan 2009a).

After detailed assessment of the remaining reports, 25 studies (14 new eligible studies) were identified. The flow chart for the review process is shown in Figure 1.

Figure 1.

Study selection flow diagram

Included studies

This review included 25 studies that involved 8289 participants. One study included relevant subsets of haemodialysis and peritoneal dialysis patient data and for purpose of the analyses have been identified as Saltissi HD 2002 and Saltissi PD 2002 respectively.

There were 14 new studies included in this update (Ahmadi 2005; Angel 2007; Arabul 2008; AURORA Study 2005; Burmeister 2006; Han 2011; SHARP Study 2010; Soliemani 2011; Tse 2008; van den Akker 2003; Vareesangthip 2005; Velickovic 1997; Vernaglione 2003; Yu 2007). Of these, two (AURORA Study 2005; SHARP Study 2010) were identified as ongoing studies in our 2009 review.

There were 23 studies (8166 participants) that compared statins with placebo or no treatment (4D Study 2004; Ahmadi 2005; Angel 2007; Arabul 2008; AURORA Study 2005; Burmeister 2006; Chang 2002; Diepeveen 2005; Dornbrook-Lavender 2005; Han 2011; Harris 2002; Ichihara 2002; Lins 2004; PERFECT Study 1997; Saltissi HD 2002-Saltissi PD 2002; SHARP Study 2010; Stegmayr 2005; Tse 2008; UK-HARP-I 2005; Vareesangthip 2005; Velickovic 1997; Vernaglione 2003;Yu 2007), and two (123 participants) directly compared two or more statins (Soliemani 2011; van den Akker 2003).

Study design

All included studies were RCTs; two were two-by-two factorial design with aspirin (UK-HARP-I 2005) and enalapril (PERFECT Study 1997).

Participants

All participants were undergoing dialysis.

Interventions

Five studies reported follow-up of more than six months (4D Study 2004; AURORA Study 2005; SHARP Study 2010; Stegmayr 2005; UK-HARP-I 2005). Generally, studies were small (median 42 participants; range 13 to 3023 participants); three studies enrolled more than 1000 participants undergoing dialysis (4D Study 2004; AURORA Study 2005; SHARP Study 2010).

Doses of statin (equivalent to simvastatin) were generally 20 mg (5 to 80 mg) with a median follow-up of six months (2 to 59 months) including studies reporting mortality and cardiovascular events. Non-randomised co-interventions included diet in three comparisons (Ichihara 2002; Saltissi HD 2002; Saltissi PD 2002).

Excluded studies

We excluded 28 studies: 13 were not randomised; seven did not include an appropriate intervention (other active treatment); one was a discontinued study; five were short durations (< 8 weeks); two were not conducted in dialysis populations (see Characteristics of excluded studies).

Risk of bias in included studies

Risk of bias in included studies is summarised in Figure 2 and Figure 3. The risk of bias was high in many of the included studies. Random sequence generation and allocation concealment was reported in three (12%) and four studies (16%), respectively. Participants and personnel were blinded in 13 studies (52%), and outcome assessors were blinded in five studies (20%). Complete outcome reporting occurred in nine studies (36%). Adverse events were only reported in nine studies (36%); 11 studies (44%) reported industry funding.The risk of bias was high in many included studies.

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

Allocation

Random sequence generation

Random sequence generation was only reported in 3/25 studies (4D Study 2004; SHARP Study 2010; UK-HARP-I 2005).

Allocation concealment

Allocation to randomised groups was not reported adequately: only 4/25 included studies reported allocation methodology in detail (4D Study 2004; SHARP Study 2010; Stegmayr 2005; UK-HARP-I 2005).

Blinding

Blinding methodology was well reported: 13 provided adequate details (4D Study 2004; Angel 2007; Arabul 2008; AURORA Study 2005; Burmeister 2006; Diepeveen 2005; Harris 2002; Ichihara 2002; Lins 2004; PERFECT Study 1997; Saltissi HD 2002-Saltissi PD 2002; SHARP Study 2010; UK-HARP-I 2005); six did not indicate blinding (Han 2011; SHARP Study 2010; Tse 2008; van den Akker 2003; Vareesangthip 2005; Vernaglione 2003); and six did not blind participants (Ahmadi 2005; Chang 2002; Dornbrook-Lavender 2005; Stegmayr 2005; Velickovic 1997; Yu 2007).

Incomplete outcome data

Drop-outs and losses to follow-up ranged for 0% to 32%. Seven studies were judged to be at low risk of bias (4D Study 2004; Arabul 2008; AURORA Study 2005; Diepeveen 2005; SHARP Study 2010; Stegmayr 2005; UK-HARP-I 2005), six were at high risk (Burmeister 2006; Chang 2002; Dornbrook-Lavender 2005; Harris 2002; Saltissi HD 2002-Saltissi PD 2002; van den Akker 2003), and the remaining 12 studies were unclear.

Selective reporting

Overall, nine studies (36%) reported all expected outcomes (4D Study 2004; Arabul 2008; AURORA Study 2005; Burmeister 2006; Lins 2004; Saltissi HD 2002-Saltissi PD 2002; SHARP Study 2010; Stegmayr 2005; UK-HARP-I 2005).

Other potential sources of bias

Eleven studies (44%) reported industry funding (4D Study 2004; AURORA Study 2005; Burmeister 2006; Chang 2002; Diepeveen 2005; Dornbrook-Lavender 2005; Lins 2004; PERFECT Study 1997; Saltissi HD 2002-Saltissi PD 2002; SHARP Study 2010; UK-HARP-I 2005)

Effects of interventions

See: Summary of findings for the main comparison

Statins versus placebo or no treatment

We found moderate-to-high quality evidence to indicate that statin therapy had little or no effect on risks of major cardiovascular events (Analysis 1.1 (4 studies, 7084 participants): RR 0.95, 95% CI 0.88 to 1.03), all-cause mortality (Analysis 1.2 (13 studies, 4705 participants): RR 0.96, 95% CI 0.90 to 1.02) and cardiovascular mortality (Analysis 1.3 (13 studies, 4627 participants): RR 0.94, 95% CI 0.84 to 1.06) (Summary of findings for the main comparison). Statins had little or no effect on risks of fatal or non-fatal myocardial infarction (Analysis 1.4 (3 studies, 4047 participants): RR 0.87, 95% CI 0.71 to 1.07) and had uncertain effects on fatal or non-fatal stroke (Analysis 1.5 (2 studies, 4018 participants): RR 1.29, 95% CI 0.96 to 1.72). There was no evidence of heterogeneity in these analyses (I² = 0%).

Statins had uncertain effects on adverse events, including elevation of creatine kinase (Analysis 1.6 (5 studies, 3067 participants): RR 1.25, 95% CI 0.55 to 2.83), elevated liver enzymes (Analysis 1.7 (4 studies, 3044 participants): RR 1.09, 95% CI 0.41 to 2.91), withdrawal due to adverse events (Analysis 1.8 (9 studies, 1832 participants): RR 1.04, 95% CI 0.87 to 1.25) and cancer (Analysis 1.9 (2 studies, 4012 participants): RR 0.90, 95% CI 0.72 to 1.11) (Summary of findings for the main comparison). There was no evidence of heterogeneity in these analyses (I² = 0%).

Statins significantly reduced total cholesterol (Analysis 1.10 (14 studies, 1803 participants): MD -44.86 mg/dL, 95% CI -55.19 to -34.53), LDL cholesterol (Analysis 1.11 (12 studies, 1747 participants): MD -39.99 mg/dL, 95% CI -52.46 to -27.52) and triglycerides (Analysis 1.12 (13 studies, 1692 participants): MD -18.02 mg/dL, 95% CI -33.00 to -3.04), but had uncertain effects on HDL cholesterol (Analysis 1.13 (13 studies, 1769 participants): MD 2.57 mg/dL, 95% CI -0.39 to 5.52).

Analysis of heterogeneity

We did not identify any sources of heterogeneity in the analyses for total or LDL cholesterol using prespecified subgroup analyses (dialysis type or statin type or dose, age, proportion with diabetes, baseline serum cholesterol, risk of bias (allocation concealment)). The lack of specific populations with or without cardiovascular disease at baseline in the available studies prevented subgroup analysis for the effect of statins by the presence or absence of cardiovascular disease.

Statin versus other statin

van den Akker 2003 (28 participants) compared atorvastatin (10 to 40 mg/d) with simvastatin (10 to 40 mg/d), and Soliemani 2011 compared atorvastatin, simvastatin and lovastatin directly (95 participants). Compared to simvastatin, atorvastatin treatment had uncertain effects on elevation of liver enzymes (Analysis 2.1 (1 study, 28 participants): RR 5.71, 95% CI 0.30 to 109.22), withdrawal from treatment due to adverse events (Analysis 2.2 (1 study, 63 participants): RR 2.06, 95% CI 0.20 to 21.63), total cholesterol (Analysis 2.3 (1 study, 28 participants): MD 0.23 mg/dL, 95% CI -0.35 to 0.81), LDL cholesterol (Analysis 2.4 (1 study, 28 participants): MD 0.06 mg/dL, 95% CI -0.40 to 0.52), triglycerides (Analysis 2.5 ((1 study, 28 participants): MD -0.02 mg/dL, 95% CI -0.58 to 0.54), and HDL cholesterol (Analysis 2.6 (1 study, 28 participants): 0.10 mg/dL, 95% CI -0.13 to 0.33). Data for other outcomes were not available in extractable format.

Sensitivity analyses

When analyses were restricted to studies in which follow-up data were provided for six months or more, the results were unchanged (major cardiovascular events, unchanged from primary result; all-cause mortality (7 studies, 4328 participants): RR 0.96, 95% CI 0.90 to 1.02) (4D Study 2004; AURORA Study 2005; Ichihara 2002; Han 2011; PERFECT Study 1997; Saltissi HD 2002-Saltissi PD 2002); cardiovascular mortality ((7 studies, 4247 participants): RR 0.94, 95% CI 0.84 to 1.06) (4D Study 2004; AURORA Study 2005; Ichihara 2002; Han 2011; PERFECT Study 1997; Saltissi HD 2002-Saltissi PD 2002).

Discussion

Summary of main results

This review update on the benefits and harms of statins in people treated with dialysis found that data for mortality and cardiovascular events were generally moderate-to-high quality. Statin therapy (generally at doses equivalent to 20 mg of simvastatin) reduced total serum cholesterol levels by 46 mg/dL (1.2 mmol/L) in adult dialysis patients, but had little or no effect on major cardiovascular events or mortality. Statins were found to have little or no effect on myocardial infarction and uncertain effects on the risk of stroke. Statins were also found to have uncertain effects on risks of liver dysfunction, muscle damage or cancer in people on dialysis; and toxicity data were limited by a lack of systematic reporting in half the studies. Few data were available for people treated with peritoneal dialysis. Direct head-to-head studies of different statin agents were rare and estimated effects of atorvastatin versus simvastatin were imprecise.

Overall completeness and applicability of evidence

Three large and well-conducted studies provided moderate-to-high quality data that showed consistent effects of statins on cardiovascular events in people treated with dialysis (4D Study 2004; AURORA Study 2005; SHARP Study 2010). Mortality data were assessed as moderate quality because information from SHARP Study 2010 could not be included as these were not reported in the published study separately for dialysis patients and could not be obtained from the authors on request.

The strengths of this review include consistent results for primary outcomes among studies (no evidence of heterogeneity), comprehensive systematic searching for eligible studies, rigid inclusion criteria for RCTs, and data extraction and analysis by two independent investigators. Furthermore, the possibility of publication bias was minimised by including both published and unpublished studies (such as abstracts from meetings), although we could not formally test for evidence of publication bias or small study effects due to the small numbers of available studies.

Despite comprehensive inclusion of available studies, the current evidence for statins in people treated with dialysis has some significant limitations. Studies were generally small (median number of participants was 42) and, with the exception of three large well-conducted studies (4D Study 2004; AURORA Study 2005; SHARP Study 2010), were assessed to be at high risk of bias. Studies were also generally of short duration (six months) and may not have been sufficiently powered to identify the effects of statins on clinical end points such as mortality (Briel 2006) (although the larger studies that dominated analyses provided outcome data for three to five years of treatment).

Limited data were available for adverse events, which were not systematically captured in over half of the included studies, such that potential toxicities of statins in this population remain incompletely characterised. We were unable to determine whether treatment effects were different in people on peritoneal dialysis compared with those on haemodialysis. Eight studies enrolled both haemodialysis and peritoneal dialysis patients and only one presented separate outcome data for these two populations (Saltissi HD 2002-Saltissi PD 2002). In addition, the small number of available studies meant that we were unable to explore other sources of heterogeneity in the treatment effects among studies on serum cholesterol levels, although this was a secondary (and surrogate) outcome. We could not identify whether treatment effects differed between men and women. Furthermore, we were unable to analyse the relative benefits of primary versus secondary prevention of cardiovascular events in people on dialysis, because there were too few studies specifically designed to address this question. SHARP Study 2010 evaluated a combination of simvastatin and ezetimibe, but it remains unclear whether there was an important difference in treatment effects compared with a statin alone, although it is unlikely because treatment effects were consistent among all studies for major cardiovascular events irrespective of the treatment used.

It was noteworthy that adverse mortality and cardiovascular events were not clearly prevented by statins in the dialysis population, despite clinically significant lowering of serum lipid levels. This finding is inconsistent with data from people with earlier stages of kidney disease not treated with dialysis, for which statins clearly reduce risks of death and major cardiovascular events (Palmer 2013a). It was possible that a lack of power in available studies for dialysis resulted in the small or no effects on all-cause mortality and cardiovascular events, although the inclusion of nearly 2000 events in each analysis makes this unlikely. It has previously been suggested that the choice of endpoints for major cardiovascular events in AURORA Study 2005 and 4D Study 2004 (both showing no statistical effect on cardiovascular events) were a reason for negative studies of statins in dialysis, because definitions of endpoints included a smaller proportion of modifiable vascular events. While this is possible, even with the inclusion of SHARP Study 2010 (in which cardiovascular events were predominantly occlusive vascular outcomes including revascularisation procedures), statins had little or no effect on cardiovascular outcomes. Finally, data comparing a statin with another statin regimen (different drug or different dose) were sparse for people treated with dialysis.

Quality of the evidence

Overall, data evaluating the effects of statins on mortality and cardiovascular outcomes for dialysis patients is of moderate to high quality and suggests that additional studies are unlikely to change our confidence in the estimates of effect or our confidence in these results. The estimates of treatment effect for mortality, cardiovascular mortality and major cardiovascular events are derived from studies at generally low risks of bias, are consistent between studies, are precise, and are generalisable to dialysis populations outside the RCTs. Direct head-to-head data for different statin agents are sparse and inconclusive.

Potential biases in the review process

Although this review was conducted by two or more independent authors, used a comprehensive search of the literature designed by a specialist librarian that included grey literature, and examined all potentially relevant clinical outcomes, potential biases exist in the review process.

We were unable to include data for people treated with dialysis from SHARP Study 2010 or Stegmayr 2005 for all-cause and cardiovascular mortality because reported data combined results for dialysis with earlier stages of kidney disease not treated with dialysis; separate unpublished data for dialysis populations were not available.

Many studies did not systematically report clinical outcomes: all but two either did not report or reported very few mortality events. Similarly, although meta-analyses for mortality and cardiovascular events had no discernible heterogeneity, effects of statins on serum cholesterol levels were markedly different among studies. Subgroup analyses did not identify reasons for differences, including type of dialysis or baseline serum cholesterol.

Adverse events and stroke data were limited by wider confidence intervals and treatment effects were uncertain.

Agreements and disagreements with other studies or reviews

This review analysed current evidence on statin therapy in adults treated with dialysis, updating evidence from its previous two iterations in 2004 and 2009 (Navaneethan 2004; Navaneethan 2009a). This update included 23 studies of statins versus placebo or no treatment in 8166 participants treated with dialysis and two head-to-head studies comparing two different statins.

Data from AURORA Study 2005 were included in analyses for mortality and major cardiovascular events, and data from SHARP Study 2010 informed analyses of major cardiovascular events. The effect estimates for statins on mortality and adverse events in this review were largely similar to our 2009 review (Navaneethan 2009a), finding little or no effect from statins among people treated with dialysis. The possible benefit from statins on non-fatal cardiovascular events in our 2009 review (which included one study of 1255 participants, 4D Study 2004) was not confirmed following inclusion of three additional studies and more than 5000 participants.

The finding that statins had little or no effect on mortality and cardiovascular outcomes in people treated with dialysis contrasts with a similar systematic review and meta-analysis of studies in people with earlier stages of CKD (Palmer 2013a) and a prospective meta-analysis of data of more general populations Baigent 2005. Statin therapy in people with less severe kidney disease proportionally reduced major cardiovascular events by 25% (RR 0.72, 95% CI 0.66 to 0.79) and all-cause mortality by 20% (RR 0.79, 95% CI 0.69 to 0.91) (Palmer 2013a ), and similarly reduced vascular events (RR 0.79, 95% CI 0.77 to 0.81) and all-cause mortality (RR 0.88, 95% CI 0.84 to 0.91) in people with or at risk of cardiovascular disease in the general population (Baigent 2005).

In a recent analysis using the current data we showed that treatment effects of statins on mortality and cardiovascular events differ significantly based on stage of kidney disease (data not shown; Palmer 2012). Although it is unclear why, despite equivalent lowering of serum cholesterol, statins have less effect in people treated with dialysis, reasons may relate to the competing causes of cardiovascular morbidity (known and unknown) in people treated with dialysis that cannot be modified significantly by the lipid-lowering or other pleiotropic effects of statins.

The smaller risk reductions from statins on death and cardiovascular disease in people treated with dialysis may reflect the competing mechanisms of cardiovascular disease in dialysis patients for whom vascular disease is dominated by vascular calcification, cardiomyopathy, hyperkalaemia, and sudden death, which might be modified to a lesser extent by statin therapy (ANZDATA 2009). We note that reductions in mortality were small in this meta-analysis despite end of treatment LDL cholesterol lowering by 41 mg/dL (1.1 mmol/L) on average. This small relative effect of lipid-lowering contrasts with a 12% risk reduction (95% CI 9% to 16%) for each 1 mmol/L reduction in LDL cholesterol in a meta-analysis of studies in the general population (Baigent 2005). However, because few studies in the current meta-analysis provided data for both all-cause mortality and end of treatment lipid levels, we could not be certain if larger reductions in cholesterol levels might reduce mortality to a greater extent in the dialysis population or whether more aggressive lipid-lowering approaches can be safely achieved with statin therapy.

Authors' conclusions

Implications for practice

Statins have little or no effect on mortality or major cardiovascular outcomes in adults treated with dialysis and cannot be routinely recommended to prevent cardiovascular events in this population. The body of included evidence did not address whether statin treatment should be stopped when a person commences dialysis, although the benefits associated with continued treatment are likely to be small. Risks of adverse events for statins on muscle and liver dysfunction and cancer with statin treatment remain uncertain. Insufficient data are available to understand whether treatment effects differ in the clinical setting of haemodialysis compared to peritoneal dialysis or the effect of statin therapy in patients with established vascular disease or recent vascular event.

Implications for research

Statin therapy consistently provides little or no benefit for people treated with dialysis. Despite some limitations, the evidence is generally moderate to high quality according to GRADE recommendations (Guyatt 2008), indicating further large studies may have an important impact on our confidence in the estimate of effect. Additional data for people treated with peritoneal dialysis would improve our confidence in the effects of therapy in this clinical setting. Well-designed RCTs of other interventions to reduce cardiovascular morbidity and death in people on dialysis are now required.

Acknowledgements

We acknowledge the contribution of study authors (Drs Wanner, Baigent, Diepeveen, Harris) who provided data about their studies upon request. We also thank 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 acknowledge Dr Rakesh Srivastava who contributed to a previous version of this review.

We wish to thank the referees for their comments and feedback during the preparation of this review.

Data and analyses

Download statistical data

Comparison 1. Statin versus placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Major cardiovascular events47084Risk Ratio (IV, Random, 95% CI)0.95 [0.88, 1.03]
2 All-cause mortality134705Risk Ratio (IV, Random, 95% CI)0.96 [0.90, 1.02]
3 Cardiovascular mortality134627Risk Ratio (IV, Random, 95% CI)0.94 [0.84, 1.06]
4 Fatal and non-fatal myocardial infarction34047Risk Ratio (IV, Random, 95% CI)0.87 [0.71, 1.07]
5 Fatal and non-fatal stroke24018Risk Ratio (IV, Random, 95% CI)1.29 [0.96, 1.72]
6 Elevated creatine kinase53067Risk Ratio (IV, Random, 95% CI)1.25 [0.55, 2.83]
7 Elevated liver function enzymes43044Risk Ratio (IV, Random, 95% CI)1.09 [0.41, 2.91]
8 Withdrawal due to adverse events91832Risk Ratio (IV, Random, 95% CI)1.04 [0.87, 1.25]
9 Cancer24012Risk Ratio (IV, Random, 95% CI)0.90 [0.72, 1.11]
10 Total cholesterol141803Mean Difference (IV, Random, 95% CI)-44.86 [-55.19, -34.53]
11 LDL cholesterol121747Mean Difference (IV, Random, 95% CI)-39.99 [-52.46, -27.52]
12 Triglycerides131692Mean Difference (IV, Random, 95% CI)-18.02 [-31.00, -3.04]
13 HDL cholesterol131769Mean Difference (IV, Random, 95% CI)2.57 [-0.39, 5.52]
Analysis 1.1.

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

Analysis 1.2.

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

Analysis 1.3.

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

Analysis 1.4.

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

Analysis 1.5.

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

Analysis 1.6.

Comparison 1 Statin versus placebo or no treatment, Outcome 6 Elevated creatine kinase.

Analysis 1.7.

Comparison 1 Statin versus placebo or no treatment, Outcome 7 Elevated liver function enzymes.

Analysis 1.8.

Comparison 1 Statin versus placebo or no treatment, Outcome 8 Withdrawal due to adverse events.

Analysis 1.9.

Comparison 1 Statin versus placebo or no treatment, Outcome 9 Cancer.

Analysis 1.10.

Comparison 1 Statin versus placebo or no treatment, Outcome 10 Total cholesterol.

Analysis 1.11.

Comparison 1 Statin versus placebo or no treatment, Outcome 11 LDL cholesterol.

Analysis 1.12.

Comparison 1 Statin versus placebo or no treatment, Outcome 12 Triglycerides.

Analysis 1.13.

Comparison 1 Statin versus placebo or no treatment, Outcome 13 HDL cholesterol.

Comparison 2. Statin versus another statin
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Elevated liver function enzymes1 Risk Ratio (IV, Random, 95% CI)Totals not selected
2 Withdrawal due to adverse events1 Risk Ratio (IV, Random, 95% CI)Totals not selected
3 Total cholesterol1 Mean Difference (IV, Random, 95% CI)Totals not selected
4 LDL cholesterol1 Mean Difference (IV, Random, 95% CI)Totals not selected
5 Triglycerides1 Mean Difference (IV, Random, 95% CI)Totals not selected
6 HDL cholesterol1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Statin versus another statin, Outcome 1 Elevated liver function enzymes.

Analysis 2.2.

Comparison 2 Statin versus another statin, Outcome 2 Withdrawal due to adverse events.

Analysis 2.3.

Comparison 2 Statin versus another statin, Outcome 3 Total cholesterol.

Analysis 2.4.

Comparison 2 Statin versus another statin, Outcome 4 LDL cholesterol.

Analysis 2.5.

Comparison 2 Statin versus another statin, Outcome 5 Triglycerides.

Analysis 2.6.

Comparison 2 Statin versus another statin, Outcome 6 HDL cholesterol.

Appendices

Appendix 1. Electronic search strategies

DatabaseSearch terms
CENTRAL
  1. MeSH descriptor Renal Dialysis explode all trees

  2. MeSH descriptor Hemofiltration explode all trees

  3. MeSH descriptor Kidney Failure, Chronic, this term only

  4. (dialysis):ti,ab,kw in Clinical Trials

  5. (hemodialysis or haemodialysis):ti,ab,kw in Clinical Trials

  6. (hemofiltration or haemofiltration):ti,ab,kw in Clinical Trials

  7. (hemodiafiltration or haemodiafiltration):ti,ab,kw in Clinical Trials

  8. (CAPD or CCPD or APD):ti,ab,kw in Clinical Trials

  9. (end-stage kidney or end-stage renal or endstage kidney or endstage renal):ti,ab,kw in Clinical Trials

  10. (ESKD or ESKF or ESRD or ESRF):ti,ab,kw

  11. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10)

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

  13. "hydroxymethylglutaryl-CoA reductase inhibitor":ti,ab,kw or "hydroxymethylglutaryl-CoA reductase inhibitors":ti,ab,kw in Clinical Trials

  14. "HMG CoA reductase inhibitors":ti,ab,kw in Clinical Trials

  15. "HMG CoA reductase inhibitor":ti,ab,kw in Clinical Trials

  16. (statin*):ti,ab,kw in Clinical Trials

  17. (atorvastatin):ti,ab,kw or (cerivastatin):ti,ab,kw or (dalvastatin):ti,ab,kw or (fluindostatin):ti,ab,kw or (fluvastatin):ti,ab,kw in Clinical Trials

  18. (lovastatin):ti,ab,kw or (pitavastatin):ti,ab,kw or (pravastatin):ti,ab,kw or (rosuvastatin):ti,ab,kw or (simvastatin):ti,ab,kw in Clinical Trials

  19. (rosuvastatin):ti,ab,kw in Clinical Trials

  20. (meglutol or mevinolin or monacolin or pravachol or lipex):ti,ab,kw in Clinical Trials

  21. (lipitor or zocor or mevacor or lescol or baycol):ti,ab,kw in Clinical Trials

  22. (#12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21)

  23. (#11 AND #22)

MEDLINE
  1. exp Renal Dialysis/

  2. exp Hemofiltration/

  3. Kidney Failure, Chronic/

  4. dialysis.tw.

  5. (hemodialysis or haemodialysis).tw.

  6. (hemofiltration or haemofiltration).tw.

  7. (hemodiafiltration or haemodiafiltration).tw.

  8. (CAPD or CCPD or APD).tw.

  9. (end-stage kidney or end-stage renal or endstage kidney or endstage renal).tw.

  10. (ESKD or ESKF or ESRD or ESRF).tw.

  11. or/1-10

  12. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/

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

  14. "HMG CoA reductase inhibitor$".tw.

  15. "HMG Co A reductase inhibitor$".tw.

  16. statin$.tw.

  17. atorvastatin.tw.

  18. cerivastatin.tw.

  19. dalvastatin.tw.

  20. fluindostatin.tw.

  21. fluvastatin.tw.

  22. lovastatin.tw.

  23. pitavastatin.tw.

  24. pravastatin.tw.

  25. rosuvastatin.tw.

  26. simvastatin.tw.

  27. rosuvastatin.tw.

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

  29. or/12-28

  30. and/11,29

EMBASE
  1. exp Renal Replacement Therapy/

  2. (hemodialysis or haemodialysis).tw.

  3. (hemofiltration or haemofiltration).tw.

  4. (hemodiafiltration or haemodiafiltration).tw.

  5. dialysis.tw.

  6. (CAPD or CCPD or APD).tw.

  7. Chronic Kidney Disease/

  8. Kidney Failure/

  9. Chronic Kidney Failure/

  10. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw.

  11. (ESRF or ESKF or ESRD or ESKD).tw.

  12. or/1-11

  13. exp Hydroxymethylglutaryl Coenzyme a Reductase Inhibitor/

  14. hydroxymethylglutaryl-CoA reductase inhibitor$.tw.

  15. HMG CoA reductase inhibitor$.tw.

  16. HMG Co A reductase inhibitor$.tw.

  17. statin$.tw.

  18. atorvastatin.tw.

  19. cerivastatin.tw.

  20. dalvastatin.tw.

  21. fluindostatin.tw.

  22. fluvastatin.tw.

  23. lovastatin.tw.

  24. pitavastatin.tw.

  25. pravastatin.tw.

  26. rosuvastatin.tw.

  27. simvastatin.tw.

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

  29. or/13-28

  30. and/12,29

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.

What's new

Last assessed as up-to-date: 29 February 2012.

DateEventDescription
7 May 2014AmendedMinor copy edit made to study names

History

Protocol first published: Issue 3, 2003
Review first published: Issue 4, 2004

DateEventDescription
30 July 2013New citation required and conclusions have changed14 new studies have been included
11 May 2012AmendedAuthor added: Jorgen Hegbrandt; Suetonia Palmer
1 March 2012New search has been performedUpdated search to February 2012. Ten new trials added including AURORA and SHARP. Results and conclusions updated. Conclusions generally unchanged.
21 January 2009New citation required and conclusions have changed

New studies included, additional outcomes now available.

New authors for this update.

1 July 2008AmendedConverted to new review format.

Contributions of authors

  • 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

  • Suetonia Palmer: data extraction, analysis and interpretation of data, drafting 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

  • Sagar Nigwekar: data extraction, analysis and interpretation of data, writing the final manuscript

  • 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

Vlado Perkovic is supported by a fellowship from the Heart Foundation of Australia and various grants from the Australian National Health and Medical Research Council. He has received speaker fees from Roche, Servier and Astra Zeneca, funding for a clinical trial from Baxter, and serves on Steering Committees for trials funded by Johnson and Johnson, Boehringer Ingelheim, Vitae and Abbott. His employer conducts clinical trials funded by Servier, Johnson and Johnson, Roche and Merck.

David Johnson is a consultant for Baxter Healthcare Pty Ltd and has previously received research funds from this company. He has also received speakers’ honoraria and research grants from Fresenius Medical Care and is a current recipient of a Queensland Government Health Research Fellowship. He has also received speakers' honoraria and consultancy fees from Amgen, Janssen-Cilag, Shire, Lilley, Boehringer-Ingelheim and Merck Sharpe & Dohme. He has received a research grant from Pfizer.

Suetonia Palmer received a fellowship administered by the Consorzio Mario Negri Sud from Amgen Dompe for assistance with travel for collaboration and supervision.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • SP receives a Fellowship from the Consorzio Mario Negri Sud from an unrestricted grant from Amgen Dompe, Italy.

Differences between protocol and review

The duration of treatment in included studies was reduced from 12 weeks to 8 weeks.

Differences between original review and review update

The study by Joy 2008 (included in the 2009 update of this review) is now considered to be a report of Dornbrook-Lavender 2005 and has been incorporated with the references for that study. Fiorini 1994 has now been excluded from the review because the study did not compare a statin with either another statin, placebo, or no treatment. Dogra 2007 has now been excluded because the treatment duration was only six weeks.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

4D Study 2004

Methods
  • Study design: parallel RCT

  • Time frame: March 1998 to March 2004

  • Follow-up period: 3.96 years (atorvastatin group); 3.91 years (placebo group)

Participants
  • Country: Germany

  • Setting: multicentre

  • Inclusion criteria: patients with type 2 DM aged 18 to 80 years who had been receiving maintenance HD < 2 years

  • Number (treatment/control): 619/636

  • Age (mean ± SD) years: treatment group (65.7 ± 8.3); control group (65.7 ± 8.3)

  • Sex (M/F): treatment group (333/286); control group (344/292)

  • Exclusion criteria: Levels of fasting serum LDL < 80 mg/dL or > 190 mg/dL, TG levels > 1000 mg/dL; liver function values > 3 x ULN or equal to those in patient with symptomatic hepatobiliary cholestatic disease; haematopoietic disease or systemic disease unrelated to ESKD; vascular intervention, CHF or MI within the 3 months preceding the period of enrolment; unsuccessful kidney transplantation; hypertension resistant to therapy

Interventions

Treatment group

  • Atorvastatin

    • Dose: 20 mg/d

    • Treatment duration: 6 months

Control group

  • Placebo

Outcomes
  • Primary outcome

    • Composite of death from cardiac causes, fatal stroke, nonfatal MI, or nonfatal stroke

  • Death from all causes

    • All cardiac events combined, and all cerebrovascular events combined

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

NotesIndustry funding received
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation code
Allocation concealment (selection bias)Low riskRandomisation code prepared by a central unit that was independent of local study personnel
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll analyses of primary and secondary endpoints were based on the classification by the endpoint committee that was agreed by consensus or majority vote. All committee members were blinded to treatment assignments until 13 August 2004
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants included in ITT analysis
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisLow riskITT

Ahmadi 2005

Methods
  • Study design: parallel RCT

  • Time frame: NR

  • Follow-up period: 3 months

Participants
  • Country: Iran

  • Setting: multicentre

  • Inclusion criteria: chronic HD patients CRP > 10 mg/L

  • Number (treatment/control): 14/13

  • Age (mean ± SD) years: treatment group (57 ± 8); control group (56 ± 9)

  • Sex (M/F): unclear

  • Exclusion criteria: patients with illnesses or drugs that may affect CRP levels

Interventions

Treatment group

  • Lovastatin

    • 20 mg daily

    • Treatment duration: 3 months

Control group

  • No medications

Outcomes
  • Hb levels

  • CRP levels

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 riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

Angel 2007

Methods
  • Study design: double-blinded cross-over RCT

  • Time frame: NR

  • Follow-up period: 2 months

Participants
  • Country: Mexico

  • Setting: NR

  • Inclusion criteria: CAPD patients without present or past (3 months) evidence of inflammation or anti-inflammatory drug intake (including statins or NSAIDs)

  • Age (mean ± SD) years: 54 ± 12 years

  • Sex: NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Pravastatin

    • Dose: 20 mg daily

    • Treatment duration: 2 months

Control group

  • Placebo

Outcomes
  • BMI

  • Creatinine

  • TC, LDL

  • TG

  • IL-6, CRP

NotesAbstract only publication
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
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

Arabul 2008

Methods
  • Study design: placebo-controlled RCT

  • Time frame: NR

  • Follow-up period: 8 weeks

Participants
  • Country: Turkey

  • Inclusion criteria: aged ≥ 18 years receiving either HD or PD; duration of dialysis of at least 6 months and presence of renal anaemia and dyslipidaemia

  • Setting: NR

  • Number (treatment/control): 22/18

  • Age (mean ± SD) years: treatment group (48.7 ± 11.3); control group (43.6 ± 14.4)

  • Sex (M/F): treatment group (12/10); control group (10/8)

  • Exclusion criteria: pregnancy, malignancy, presence of acute inflammatory disorders, current drug use (statins, NSAIDs, immunosuppression), liver or thyroid disease, and haemodynamic instability

Interventions

Treatment group

  • Fluvastatin

    • Dose: 40 mg twice daily

    • Treatment duration: 8 weeks

Control group

  • Placebo

Outcomes
  • TC, LDL, HDL

  • TG

  • hs-CRP

  • Prohepcidin

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
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Low riskNone
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

AURORA Study 2005

Methods
  • Study design: parallel RCT

  • Time frame: January 2003 to December 2008

  • Follow-up period: mean 3.2 years

Participants
  • Country: International

  • Setting: multicentre

  • Inclusion criteria: patients treated with HD or HF for at least 3 months and aged 50 to 80 years

  • Number (treatment/control): 1389/1384

  • Age (mean ± SD) years: treatment group (64.1 ± 8.6); control group (64.3 ± 8.7)

  • Sex (M/F): treatment group (851/538); control group (812/512)

  • Exclusion criteria: statins therapy 6 months, expected kidney transplantation within 1 year, and serious haematologic, neoplastic, gastrointestinal, infectious, or metabolic disease (excluding diabetes) predicted to limit life expectancy to < 1 year; history of malignant condition, active liver disease (indicated by an AST level > 3 x ULN), uncontrolled hypothyroidism, and an unexplained elevation in CK level > 3 x ULN

Interventions

Treatment group

  • Rosuvastatin

    • Dose: 10 mg

    • Treatment duration: mean 3.2 years, maximum 5.6 months

Control group

  • Placebo

Outcomes
  • Primary endpoint: Time to a major cardiovascular event defined as non-fatal MI, non-fatal stroke or death from cardiovascular causes

  • Secondary endpoints: all-cause mortality, cardiovascular event–free survival (i.e. freedom from non-fatal MI, non-fatal stroke, cardiovascular cause mortality, and all-cause mortality), procedures performed for stenosis or thrombosis of the vascular access for long-term HD (arteriovenous fistulas and grafts only), and coronary or peripheral revascularisation, death from cardiovascular causes, and death from non-cardiovascular causes

NotesIndustry funding received
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 riskAll MIs, strokes, and deaths were reviewed and adjudicated by a clinical endpoint committee whose members were unaware of the randomised treatment assignments to ensure consistency of the event diagnosis
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients were lost to follow-up
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisLow riskConducted

Burmeister 2006

Methods
  • Study design: double-blind placebo controlled RCT

  • Time frame: NR

  • Follow-up period: 3 months

Participants
  • Country: Brazil

  • Setting: single centre

  • Inclusion criteria: patients undergoing regular 4 hour HD sessions 3 x week for at least 3 months

  • Number (treatment/control): 28/31

  • Age (mean ± SD) years: treatment group (53.7 ± 16.6); control group (60.1 ± 13.8)

  • Sex (M/F): treatment group (16/12); control group (21/10)

  • Exclusion criteria: uncontrolled DM (HbA1C > 9%), fasting LDL-C > 190 mg/dL, TG > 400 mg/dL, impaired hepatic function (aminotransferases > 3 x ULN reference value, or symptomatic hepatobiliary cholestatic disease), elevated SCr phosphokinase levels, use of beta-blockers, any active infectious disease, past or present malignancies, acute myocardial insufficiency, or any other systemic disease not related to CRF, and previous usage of any lipid-lowering drug for the last 3 months

Interventions

Treatment group

  • Rosuvastatin

    • Dose: 10 mg/d

    • Treatment duration: 3 months

Control group

  • Placebo

Outcomes
  • Serum lipids (TC, LDL, HDL, TG)

  • Apo B

  • hs-CRP

NotesIndustry funding received
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
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Low risk3/59 (5%) lost to follow-up
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisHigh riskNot conducted

Chang 2002

Methods
  • Study design: parallel RCT

  • Time frame: 2000 to 2001

  • Follow-up period: 8 weeks

Participants
  • Country: South Korea

  • Setting: single centre

  • Inclusion criteria: HD patients with TC > 200 mg/dL

  • Number (treatment/control): 31/31

  • Age (mean ± SD) years: treatment group (63 ± 11); control group (60 ± 12)

  • Sex (M/F): treatment group (8/23); control group (10/21)

  • Exclusion criteria: active inflammation; infection; on other hypolipidaemic agents; other intercurrent illnesses

Interventions

Treatment group

  • Simvastatin

    • Dose: 20 mg

    • Treatment duration: 2 months

Control group

  • Placebo

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

  • Lipoprotein profiles and CRP levels

NotesIndustry funding received
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
High riskNot blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk4/62 (6.5%) patients did not complete study
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisHigh riskNot conducted

Diepeveen 2005

Methods
  • Study design: placebo controlled RCT

  • Time frame: NR

  • Study duration: 12 weeks

Participants
  • Country: Netherlands

  • Setting: single centre

  • Inclusion criteria: clinically stable non-diabetic patients on dialysis therapy; without manifest CVD

  • Number (group 1/group 2/group 3/control): 13/10/11/10

    • HD (23); PD (21)

  • Age (mean ± SD) years group 1 (46 ± 15); group 2 (47 ± 16); group 3 (51 ± 20); control group (51 ± 18)

  • Sex (M/F): group 1 (9/4); group 2 (8/2); group 3 (5/6); control group (8/2)

  • Exclusion criteria: NR

Interventions

Treatment group 1

  • Atrovastatin + alfa-tocopherol placebo

    • Dose: 40 mg, once/d

Treatment group 2

  • Alfa-tocopherol + atorvastatin placebo

    • Dose: 800 IU, once/d

Treatment group 3

  • Alfa-tocopherol

    • Dose: 800 IU, once/d

  • Atorvastatin

    • Dose: 40 mg, once/d

Control group

  • Alfa-tocopherol placebo + atorvastatin placebo

Treatment duration: 3 months

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

Notes

Study included 4 arms and we compared treatment group 1 and the control group (see interventions)

Industry funding received

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
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete follow-up
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisLow riskConducted

Dornbrook-Lavender 2005

Methods
  • Study design: unblinded parallel RCT

  • Time frame: June 2001 to October 2002

  • Follow-up period: 20 weeks

Participants
  • Country: USA

  • Setting: two centres

  • Inclusion criteria: HD patients with normal liver function, CK levels and LDL > 100 mg/dL

  • Number (treatment/control): 9/10

  • Age (mean ± SD) years: treatment group (70 ± 15); control group (62 ± 15)

  • Sex (M/F): treatment group (3/6); control group (4/6)

  • Exclusion criteria: pregnancy; known allergies to statin; history of alcohol use

Interventions

Treatment group

  • Atorvastatin

    • Dose: 10 mg

  • Treatment duration: 20 weeks

Control group

  • No treatment

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

  • Lipoprotein profiles and CRP levels

NotesIndustry funding received
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
High risk6/19 (32%) did not complete study
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisHigh riskNot conducted

Han 2011

Methods
  • Study design: open-label prospective RCT

  • Time frame: January 2008 to December 2008

  • Follow-up period: 6 months

Participants
  • Country: Korea

  • Setting: single centre

  • Inclusion criteria: aged > 20 years and maintained on PD > 3 months

  • Number (treatment/control): 57/57

  • Age (mean ± SD) years: 48.8 ± 11.0

  • Sex (M/F): 55/69

  • Exclusion criteria: patients with overt infection during 3 months prior to study and history of malignancy or other chronic inflammatory disease, such as systemic lupus erythematosus or rheumatoid arthritis

Interventions

Treatment group

  • Rosuvastatin

    • Dose: 10 mg/d

  • Valsartan

    • Dose: 80 mg/d

  • Treatment duration: 6 months

Control group

  • Valsartan

    • Dose: 80 mg/d

    • Treatment duration: 6 months

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

  • Clinical adverse events along with ALT, AST, CK monitoring

  • All-cause mortality

  • Inflammatory markers, oxidative stress and pulse wave velocity

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
High risk36/114 patients (32%) withdrawn
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

Harris 2002

Methods
  • Study design: RCT

  • Time frame: November 1998 to February 2000

  • Follow-up period: 16 weeks

Participants
  • Country: UK/Ireland

  • Setting: 33 centres

  • Inclusion criteria: CAPD or APD for at least 3 months, TC > 200 mg/dL, LDL > 135 mg/dL, dyslipidaemia uncontrolled by other lipid-lowering therapy for at least 4 weeks

  • Number (treatment/control): 82/94

  • Age (mean ± SD) years: treatment group (56.7 ± 15.4); control group (57.5 ± 13.5)

  • Sex (M/F): treatment group (47/35); control group (42/52)

  • Exclusion criteria: active liver disease or Increased ALT or AST (> 3 x ULN), concurrent therapy with immunosuppressants, uncontrolled DM, patient receiving other lipid-lowering agents, patients with history of PTCA, CABG within 3 months, alcohol abuse, clinical evidence of inflammatory muscle disease and TC > 310 mg/dL)

Interventions

Treatment group

  • Atorvastatin

    • Dose: 10 mg; dose increased to 40 mg as needed to achieve LDL < 135 mg/dL

    • Treatment duration: 16 weeks

Control group

  • Placebo

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

  • Clinical adverse events along with ALT, AST, CK monitoring

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
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk130/153 (85%) completed the study
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisHigh riskNot conducted

Ichihara 2002

Methods
  • Study design: RCT

  • Time frame: NR

  • Follow-up period: 6 months

Participants
  • Country: Japan

  • Setting: single centre

  • Inclusion criteria: HD for at least 6 months, with no pre-existing CVD, secondary hyperparathyroidism and fasting blood glucose > 110 mg/dL

  • Number (treatment/control): 12/10

  • Age (mean ± SD) years: treatment group (65.8 ± 3.0); control group (64.3 ± 3.7)

  • Sex (M/F): treatment group (8/4); control group (6/4)

  • Exclusion criteria: premenopausal women, patients on HRT, alcohol consumption

Interventions

Treatment group

  • Fluvastatin

    • Dose: 10 mg

    • Treatment duration: 6 months

Control group

  • Placebo

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

  • Pulse wave velocity, CRP levels

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
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

Lins 2004

Methods
  • Study design: placebo-controlled RCT

  • Time frame: March 1998 to October 1999

  • Follow-up period: 12 weeks

Participants
  • Country: Belgium

  • Setting: multicentre (10 HD centres)

  • Inclusion criteria: TC > 210 mg/dL and total TG > 500 mg/d

  • Number (treatment/control): 23/19

  • Age (mean ± SD) years: treatment group (63.8 ± 12.3); control group (65.2 ± 9.3)

  • Sex (male): treatment group (92%); control group (73%)

  • Exclusion criteria: pregnancy, breastfeeding, LFT > 3 x ULN, HbA1C > 10%

Interventions

Treatment group

  • Atorvastatin

    • Dose: forced 4 weekly titration of 10 to 20 mg and up to 40 mg once daily

    • Treatment duration: 12 weeks

Control group

  • Placebo

Outcomes
  • Lipid parameters (TC, TG, LDL, HDL) and Apo (A-I, A-II, B, E, CIII)

  • Adverse events (specific details unknown)

NotesIndustry funding received
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
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisUnclear riskNR

PERFECT Study 1997

Methods
  • Study design: parallel RCT

  • Duration: NR

  • Follow-up: 6 months

Participants
  • Country: New Zealand

  • Setting: multicentre

  • Inclusion criteria: HD and CAPD patients

  • Number (treatment/control): simvastatin (24); placebo (29)

  • Age (mean ± SD) years: 50 ± 15

  • Sex (M/F): 32/21

  • Exclusion criteria: definite indication for statin or ACEi, known allergy to either drug, planned transplant from living related donor in next 12 months, CHF, severe valve disease, supine systolic BP > 100 mm Hg or significant postural hypotension, uncontrolled hypertension, hepatitis B or C positive, AST or ALT > 2 X ULN, treatment with cyclosporin or a fibrate, life threatening illness or serious debilitating disease other than CKD

Interventions

Treatment group (B)

  • Simvastatin

    • Dose: 10 mg/d

  • Placebo enalapril

  • Treatment duration: 6 months

Control group (D)

  • Placebo simvastatin

  • Placebo enalapril

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

  • Apo A, Apo B

Notes

Study had four arms

  • Group A: simvastatin plus enalapril

  • Group B: simvastatin plus placebo enalapril

  • Group C: placebo simvastatin plus enalapril

  • Group D: placebo simvastatin plus placebo enalapril

Industry funding received

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Unclear risk"...the code identifying the treatment received by individual patients was maintained by a person remote from the investigators."
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
Unclear riskNR
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisLow riskConducted

Saltissi HD 2002

Methods
  • Study design: stratified, placebo-controlled RCT

  • Time frame: NR

  • Follow-up period: 24 weeks

Participants
  • Country: Australia

  • Setting: single centre

  • Inclusion criteria: HD or CAPD for 9 months, non-HDL > 135 mg/dL, LDL > 116 mg/dL, TG < 600 mg/dL

  • Number (treatment/control): 22/12

  • Age (mean ± SD) years: treatment group (59.5 ± 13.9); control group (62.8 ± 9.6)

  • Sex (M/F): treatment group (6/16); control group (5/7)

  • Exclusion criteria: impaired hepatic function; elevated creatine phosphokinase; myocardial insufficiency; uncontrolled DM; active infection; malignancy; treatment with other lipid-lowering agents

Interventions

Treatment group

  • Simvastatin

    • Dose: 5 mg and dose was increased to 20 mg as needed to achieve non-HDL < 135 mg/dL

  • Treatment duration: 24 weeks

Control group

  • Placebo

OutcomesLipid parameters (TC, LDL, HDL, TG, Lp (a), Apo A1)
Notes

This is the same study as Saltissi PD 2002

Industry funding received

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
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk42/57 patients (74%) completed study
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisHigh riskNot conducted

Saltissi PD 2002

Methods
  • Study design: stratified, placebo-controlled RCT

  • Time frame: NR

  • Follow-up period: 24 weeks

Participants
  • Country: Australia

  • Setting: single centre

  • Inclusion criteria: HD or CAPD for 9 months, non-HDL > 135 mg/dL, LDL > 116 mg/dL, TG < 600 mg/dL

  • Number (treatment/control): 16/7

  • Age (mean ± SD) years: treatment group (55.3 ± 13.3); control group (61.0 ± 7.6)

  • Sex (M/F): treatment group (4/12); control group (1/6)

  • Exclusion criteria: impaired hepatic function; elevated creatine phosphokinase; myocardial insufficiency; uncontrolled DM; active infection; malignancy; treatment with other lipid-lowering agents

Interventions

Treatment group

  • Simvastatin

    • Dose: 5 mg and dose was increased to 20 mg as needed to achieve non-HDL < 135 mg/dL

  • Treatment duration: 24 weeks

Control group

  • Placebo

OutcomesLipid parameters (TC, LDL, HDL, TG, Lp (a), Apo A1)
Notes

This is the same study as Saltissi HD 2002

Industry funding received

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
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
High risk42/57 patients (74%) completed study
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisHigh riskNot conducted

SHARP Study 2010

Methods
  • Study design: double blind RCT

  • Time frame: August 2003 to August 2010

  • Follow-up period: 4.9 years

Participants
  • Country: multinational

  • Setting: multicentre

  • Inclusion criteria: 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 (HD or PD); men or women aged ≥ 40 years

  • Number (treatment/control): 1533/1490 (dialysis patients only)

  • Age (mean ± SD) years: treatment group (62 ± 12); control group (62 ± 12)

  • Sex (M): treatment group (2915, 63%); control group (2885, 62%)

Exclusion criteria

  • Confirmed history of MI or coronary revascularisation procedure

  • Functioning renal transplant or living donor renal transplant planned

  • < 2 months since presentation as an acute uraemic emergency

  • Confirmed history of chronic liver disease or abnormal liver function (i.e. ALT N1.5 x ULN or, if ALT not available, AST N1.5 x ULN) (patients with history of hepatitis were eligible if these limits not exceeded)

  • Evidence of active inflammatory muscle disease (e.g. dermatomyositis, polymyositis) or CK N3 x ULN

  • Confirmed previous adverse reaction to a statin or to ezetimibe

  • Concurrent treatment with a contraindicated drug:

    • Hydroxymethylglutaryl–coenzyme A reductase inhibitor (statin)

    • Ezetimibe

    • Fibric acid derivative (fibrate)

    • Nicotinic acid

    • Cyclosporin

    • Macrolide antibiotic (erythromycin, clarithromycin)

    • Systemic use of imidazole or triazole antifungals (e.g. itraconazole, ketoconazole)

    • Protease-inhibitors (e.g. antiretroviral drugs for HIV infection)

    • Nefazodone

  • Childbearing potential (i.e. premenopausal woman not using a 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 participate in trial treatments for the duration of the study (e.g. severe respiratory disease, history of cancer other than non-melanoma skin cancer, or recent history of alcohol or substance misuse)

Interventions

Treatment group

  • Simvastatin

    • Dose: 20 mg/d

  • Ezetimibe

    • Dose: 10 mg/d

  • Treatment duration: 4.9 years

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, AST

Notes

Only dialysis patients data from the SHARP Study 2010 trial have been included in this review

Industry funding received

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
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisLow riskConducted

Soliemani 2011

Methods
  • Study design: double-blinded RCT

  • Time frame: 2009

  • Follow-up period: 2 months

Participants
  • Country: Iran

  • Setting: single centre

  • Inclusion criteria: HD patients aged < 70 years

  • Number (treatment 1/treatment 2/treatment 3): 31/32/32

  • Age (mean ± SD) years: treatment group 1 (49.8 ± 12.3); treatment group 2 (47.2 ± 9.4); treatment group 3 (51.6 ± 14.2)

  • Sex (M/F): treatment group 1 (21/10); treatment group 2 (19/13); treatment group 3 (22/10)

  • Exclusion criteria: infectious, inflammatory or rheumatic diseases during the past 2 months (based on physician's records); MI, CVA, or any indisposition during the past 3 months; and having been receiving statins, NSAIDs, corticosteroid, or other immunological inhibitors (e.g. cyclosporin) within the past 3 months

Interventions

Treatment group 1

  • Atorvastatin

    • Dose: 10 mg/d

  • Treatment duration: 2 months

Treatment group 2

  • Simvastatin

    • Dose: 20 mg/d

  • Treatment duration: 2 months

Treatment group 3

  • Lovastatin

    • Dose: 40 mg/d

  • Treatment duration: 2 months

Outcomes
  1. CRP

  2. IL-6

  3. TC, LDL, HDL

  4. 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 riskDouble blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskUnclear

Stegmayr 2005

Methods
  • Study design: open RCT

  • Time frame: from February 1998

  • Follow-up period: 5 years

Participants
  • Country: Sweden

  • Setting: multicentre

  • Inclusion criteria: GFR < 30 mL/min/1.73 m²

  • Number (treatment/control): 70/73

  • Age (mean ± 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 on waiting list for transplantation; those on protein-restricted diet < 40 g protein/day; poor compliance to medication and follow-up; history of progressive malignancy and life expectancy < 6 months

Interventions

Treatment group

  • Atorvastatin

    • Dose: 10 mg/d

  • Treatment duration: 35 ± 20.1 months (range 1 to 67 months)

Control group

  • Placebo

  • Treatment duration: 31 ± 21.4 months (range 0.5 to 69 months)

Outcomes
  • All-cause mortality

  • AMI

  • need for PTCA

  • CABG

  • Lipid profile

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNR
Allocation concealment (selection bias)Low riskRandomisation 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
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisLow riskConducted

Tse 2008

Methods
  • Study design: RCT

  • Time frame: NR

  • Follow-up period: 12 weeks

Participants
  • Country: Hong Kong

  • Setting: single centre

  • Inclusion criteria: dialysis patients with elevated baseline hs-CRP (≥1.50 mg/L) without concomitant infection or inflammatory conditions

  • Number (treatment/control): NR

  • Age: NR

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Atorvastatin

    • Dose: 10 mg/d

  • Treatment duration: 12 weeks

Control group

  • Placebo

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

  • hs-CRP

Notes
  • Letter to the editor

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
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

UK-HARP-I 2005

Methods
  • Study design: RCT

  • Time frame: October 1999 to March 2001

  • Follow-up: 1 year

Participants
  • Country: UK

  • Setting: multicentre

  • Inclusion criteria: Adult patients on dialysis (subset of study)

  • Number of dialysis patients (treatment/control): 38/35

    • HD patients (treatment/control): 17/17

    • PD patients (treatment/control): 21/18

  • Age: NR

  • Sex: NR

  • Exclusion criteria: Patients on statins; recent history of acute uraemia; chronic liver disease

Interventions

Treatment group

  • Simvastatin

    • Dose 20 mg/d

  • Treatment duration: 12 months

Control group

  • Placebo

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

  • Safety outcomes (hepatic and muscle toxicity)

Notes
  • Study included predialysis, dialysis (HD and PD) and kidney transplant recipients

  • Data for age and sex were only reported for the complete randomised groups

  • Industry funding received

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskMinimised randomisation used to balance the treatment groups; 2 x 2 factorial design
Allocation concealment (selection bias)Low riskRandomisation was 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 (98.7%) patients completed follow-up
Selective reporting (reporting bias)Low riskPublished reports included all expected outcomes
ITT analysisLow riskConducted

van den Akker 2003

Methods
  • Study design: RCT

  • Time frame: NR

  • Follow-up period: 5 months

Participants
  • Country: Netherlands

  • Setting: single centre

  • Inclusion criteria: HD patients

  • Number (treatment 1/treatment 2): 28/10

  • Age (years): treatment group 1 (65.8); treatment group 2 (66)

  • Sex (M/F): NR

  • Exclusion criteria: DM, hypothyroidism or familial dyslipidaemia; patients using beta blockers

Interventions

Treatment group 1

  • Simvastatin

    • Dose: 10 mg to 40 mg

  • Treatment duration: 18 weeks

Treatment group 2

  • Atorvastatin

    • Dose: 10 to 40 mg

  • Treatment duration: 18 weeks

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

  • Lipoproteins

  • LDL particle heterogeneity

  • hs-CRP

  • Markers of in vivo LDL oxidation

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
Low risk2/28 patients (7%) discontinued therapy
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisHigh riskNot conducted

Vareesangthip 2005

Methods
  • Study design: RCT

  • Time frame: NR

  • Follow-up period: 4 months

Participants
  • Country: Thailand

  • Setting: single centre

  • Inclusion criteria: HD patients

  • Number (treatment/control): 10/10

  • Age: NR

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Simvastatin

    • Dose: 10 mg

  • Treatment duration: 4 months

Control group

  • Placebo

Outcomes
  • CRP

  • ESR

  • Lipid parameters

  • Erythrocyte sodium lithium countertransport

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
Unclear riskNR
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

Velickovic 1997

Methods
  • Study design: cross-over RCT

  • Time frame: Unclear

  • Follow-up period: 24 weeks

Participants
  • Country: Yugoslavia

  • Setting: single centre

  • Inclusion criteria: CAPD patients

  • Number: 13

  • Age (mean ± SD) years: 55.2 ± 8.0

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group

  • Simvastatin

    • Dose: 20 mg

  • Treatment duration: 24 weeks

Control group

  • Placebo

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

  • Adverse events: Liver and muscle enzymes

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 riskInvestigators not blinded
Blinding of outcome assessment (detection bias)
All outcomes
High riskNot blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNR
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

Vernaglione 2003

Methods
  • Study design: prospective RCT

  • Time frame: NR

  • Follow-up period: 6 months

Participants
  • Country: Italy

  • Setting: single centre

  • Inclusion criteria: serum CRP levels ≥ 3 mg/L (42.2% of the entire population) undergoing HD treatment for at least 6 months, had patent autologous vascular access, and treated with the same dialyser in the last 3 months

  • Number (treatment/control): 16/17

  • Age (mean ± SD) years: treatment group (65.2 ± 11.8); control group (65.5 ± 10.2)

  • Sex (M/F): treatment group (4/12); control group (8/9)

  • Exclusion criteria: patients with liver diseases, neoplasms, recent surgical interventions or trauma, sepsis, chronic inflammatory diseases, and those who had received prolonged treatments with NSAIDs and/or steroids and/or vitamins E or C

Interventions

Treatment group

  • Atorvastatin

    • Dose: 10 mg/d

  • Treatment duration: 6 months

Control group

  • Placebo

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

  • Serum CRP

  • Serum albumin

  • Serum urea, SCr

  • Adverse events: Serum ALT, AST, glutamyltransferase, CK, lactate dehydrogenase

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
Selective reporting (reporting bias)High riskPublished reports did not include all expected outcomes
ITT analysisUnclear riskNR

Yu 2007

  1. a

    ALT - alanine aminotransferase; APD - automated peritoneal dialysis; Apo - apoprotein; AST - aspartate aminotransferase; AMI - acute myocardial infarction; BP - blood pressure; CABG - coronary artery bypass graft; CAPD - continuous ambulatory peritoneal dialysis; CHF - chronic heart failure; CK - creatine kinase; CKD - chronic kidney disease; CRP - C-reactive protein; CVA - cerebrovascular accident; CVD - cardiovascular disease; DM - diabetes mellitus; ESKD - end-stage kidney disease; ESR - erythrocyte sedimentation rate; HD - haemodialysis; HDL - high-density lipoprotein; HRT - hormone replacement therapy; hs-CRP - highly-sensitive CRP; IL-6 - interleukin 6; ITT - intention-to-treat; LDL - low-density lipoprotein; LFT - liver function test; MI - myocardial infarction; NR - not reported; NSAIDs - non-steroidal anti-inflammatory drugs; PD - peritoneal dialysis; PTCA - percutaneous transluminal coronary angioplasty; SCr - serum creatinine; TC - total cholesterol; TG - triglycerides; ULN - upper limit of normal

Methods
  • Study design: RCT

  • Time frame: NR

  • Follow-up period: 8 weeks

Participants
  • Country: South Korea

  • Setting: NR

  • Inclusion criteria: HD or PD therapy and TC > 170 mg/dL

  • Number (treatment 1/treatment 2): NR

  • Age: NR

  • Sex (M/F): NR

  • Exclusion criteria: NR

Interventions

Treatment group 1

  • Simvastatin

    • Dose: 10 mg/d

  • Ezetimibe

    • Dose: 10 mg/d

  • Treatment duration: 8 weeks

Treatment group 2

  • Ezetimibe

    • Dose: 10 mg/d

  • Treatment duration: 8 weeks

Outcomes
  • CRP

  • TC, LDL

  • Fibrinogen, Von Willebrand factor, D-dimer

NotesAbstract publication 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 riskNot blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNR
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear
Selective reporting (reporting bias)High riskPublication reports did not provide all expected outcomes
ITT analysisUnclear riskNR

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Akcicek 1996Not RCT (prospective cohort study)
Bunio 2004Active comparator (not statin)
Cappelli 2000Active comparator (not statin)
Cheng 1995Active comparator (not statin)
CHORUS Study 2001Study discontinued
Dogra 2007Short duration
Fiorini 1992Not RCT
Fiorini 1994Active comparator (not statin)
Hufnagel 2000Not RCT (prospective cohort study)
Khajehdehi 2000Not appropriate intervention
Kim 2009Not dialysis
Kishimoto 2010Not RCT
Li 1993Study duration < 8 weeks
Lins 2003Study duration 2 weeks
Lynoe 2004Not appropriate intervention
Malyszko 2002Not RCT (prospective cohort study)
Nishikawa 1999Not RCT (prospective cohort study)
Nishizawa 1995Not RCT (prospective cohort study)
Rincon 1995Not RCT
Samuelsson 2002Not dialysis
Sezer 2004Duration 1 month
Singh 2002Duration 4 weeks
Tani 1998Not RCT (prospective cohort study)
UK-HARP-II 2006Not appropriate intervention
Wanner 1991Not RCT (prospective cohort study)
Wanner 1992Not RCT (prospective cohort study)
Yigit 2004Not RCT
Zhu 2000Not RCT (prospective cohort study)

Characteristics of ongoing studies [ordered by study ID]

Nardi 2005

Trial name or titlePrévention par la pravastatine de la dégradation de l’état nutritionnel des patients hémodialysés présentant un état inflammatoire chronique
MethodsRandomised trial, multicentre, double-blinded, placebo-controlled
ParticipantsHaemodialysis > 3 months, aged > 18 years and < 80 years, serum albumin < 40 g/L, and existence of chronic inflammation defined as CRP 10 to 50 mg/L on two separate occasions, without an identifiable cause
InterventionsPravastatin 20 to 40 mg/d or placebo for 12 months
OutcomesInflammation
Starting date2005
Contact informationCHU de Bordeaux, hôpital Pellegrin, Département de Néphrologie–Hémodialyse, 1, place Amélie-Raba-Léon, 33076 Bordeaux Cedex, France
Notes 

NCT00291863

Trial name or titleSimvastatin effect on end stage renal failure patients treated by peritoneal dialysis
MethodsRandomised, parallel group, double-blind
Participants18 to 80 years, ESKD, LDL cholesterol > 100 mg/dL
InterventionsSimvastatin
OutcomesEndothelial venodilation, inflammatory markers, lipoproteins, oxidative stress
Starting dateFebruary 2006
Contact informationMaristela Bohlke
NotesRecruitment status of this study is unknown because the information has not been verified recently

NCT00858637

Trial name or titleEfficacy and safety study of MCI-196 versus simvastatin for dyslipidaemia in chronic kidney disease (CKD) subjects on dialysis
MethodsPhase III, multicentre, double-blind, double-dummy, randomised, flexible-dose, comparative study of MCI-196 versus simvastatin
Participants> 18 years, male or female, stable dialysis, negative pregnancy test and appropriate contraception
InterventionsSimvastatin, MCl-196, or placebo
OutcomesChange in LDL cholesterol, change in total cholesterol, HDL cholesterol, triglycerides and additional lipid parameters, change in phosphorus (P), Calcium (Ca), calcium-phosphorus ion product (PxCa) and parathyroid hormone (PTH), vital signs, adverse events, and laboratory values
Starting dateMarch 2009
Contact informationMitsubishi Tanabe Pharma Corporation
NotesUnclear contact information

NCT00999453

  1. a

    LDL - low density lipoprotein; HDL - high density lipoprotein

Trial name or titleThe effects of lowering low-density lipoprotein cholesterol levels to new targets on cardiovascular complications in peritoneal dialysis patients
MethodsRandomised, parallel group, open label
Participants20 to 70 years, treated with peritoneal dialysis for 3 or more months, LDL cholesterol 100 mg/dL or higher within 3 months and total cholesterol level 220 mg/dL or higher
InterventionsEither aggressive targets of LDL cholesterol of 70 mg/dL or current standard targets of LDL cholesterol of 100 mg/dL
OutcomesCardiovascular complication including acute coronary syndrome, cerebrovascular infarction and cardiovascular death
Starting dateOctober 2009
Contact informationShin-Wook Kang
NotesThis study is currently recruiting participants

Ancillary