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استفاده از مهارکننده‌های HMG CoA ردوکتاز (استاتین‌ها) در بیماران تحت دیالیز

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چکیده

پیشینه

افراد مبتلا به بیماری کلیوی پیشرفته که تحت دیالیز قرار دارند، با نرخ بیشتر مرگ‌ومیر یا مورتالیتی ناشی از بیماری قلبی‌عروقی روبه‌رو هستند که به‌طور قابل توجهی بیشتر از جمعیت عمومی است. مطالعاتی که مزایای استاتین‌ها (مهارکننده‌های HMG CoA ردوکتاز) را ارزیابی کرده‌اند، نتایج متناقضی را برای افراد تحت دیالیز گزارش می‌کنند و متاآنالیزهای موجود قدرت کافی را برای تعیین اینکه تاثیرات استاتین‌ها با شدت بیماری کلیوی متفاوت هستند یا خیر، نداشته‌اند. اخیرا، اطلاعات بیشتری در مورد اثرات استاتین‌ها در بیماران دیالیزی در دسترس قرار گرفته‌اند. این یک نسخه به‌روز شده از مروری است که نخستین‌بار در سال 2004 منتشر، و آخرین‌بار در سال 2009 به‌روز شد.

اهداف

ارزیابی فواید و مضرات استفاده از استاتین در بزرگسالان نیازمند به دریافت دیالیز (همودیالیز یا دیالیز صفاقی).

روش‌های جست‌وجو

از طریق برقراری ارتباط با هماهنگ‌کننده جست‌وجوی کارآزمایی‌ها و با استفاده از واژگان و اصطلاحات جست‌وجوی مرتبط با این مرور، پایگاه ثبت تخصصی گروه کلیه در کاکرین را تا تاریخ 29 فوریه 2012 جست‌وجو کردیم.

معیارهای انتخاب

کارآزمایی‌های تصادفی‌سازی و کنترل‌شده (randomised controlled trials; RCTs) و شبه‐RCTهایی برای ورود در نظر گرفته شدند که تاثیرات استاتین‌ها را با دارونما (placebo)، عدم درمان، مراقبت استاندارد یا دیگر استاتین‌ها بر مرگ‌ومیر، حوادث قلبی‌عروقی و سمیّت مرتبط با درمان در بزرگسالان تحت درمان با دیالیز مقایسه کردند.

گردآوری و تجزیه‌وتحلیل داده‌ها

دو یا چند نویسنده مرور به‌طور مستقل از هم داده‌ها را استخراج و خطر سوگیری (bias) را ارزیابی کردند. تاثیرات درمان با استفاده از یک مدل اثرات تصادفی (random‐effects model) خلاصه شده و آنالیز‌های زیرگروه برای کشف منابع ناهمگونی (heterogeneity) انجام شدند. تاثیرات درمان به‌ صورت تفاوت میانگین (MD) برای پیامدهای پیوسته (continuous outcome) و خطرات نسبی (RR) برای پیامدهای دو حالتی (dichotomous) با 95% فواصل اطمینان (CI) بیان شدند.

نتایج اصلی

سطح خطر سوگیری (bias) در بسیاری از مطالعات واردشده بالا بود. تولید تصادفی توالی (random sequence generation) و پنهان‏‌سازی تخصیص (allocation concealment) به ترتیب در سه (12%) و چهار (16%) مطالعه گزارش شد. شرکت‌کنندگان و پرسنل در 13 مطالعه (52%) و ارزیابان پیامد در پنج مطالعه (20%) کورسازی شدند. گزارش‌دهی کامل از پیامد در نه مطالعه (36%) دیده شد. عوارض جانبی فقط در نه مطالعه (36%) گزارش شدند؛ 11 مطالعه (44%) استفاده از بودجه صنعت را گزارش کردند.

تعداد 25 مطالعه (8289 شرکت‌کننده) را در این آخرین به‌روزرسانی گنجاندیم؛ 23 مطالعه (24 مقایسه، 8166 شرکت‌کننده) استاتین‌ها را با دارونما یا عدم درمان، و دو مطالعه (123 شرکت‌کننده) استاتین‌ها را مستقیما با یک یا چند استاتین دیگر مقایسه کردند. استاتین‌ها تاثیری اندک یا عدم تاثیر بر حوادث قلبی‌عروقی عمده (4 مطالعه، 7084 شرکت‌کننده: RR: 0.95؛ 95% CI؛ 0.88 تا 1.03)، مورتالیتی به هر علتی (all‐cause mortality) (13 مطالعه؛ 4705 شرکت‌کننده: RR: 0.96؛ 95% CI؛ 0.90 تا 1.02)، مرگ‌ومیر قلبی‌عروقی (13 مطالعه، 4627 شرکت‌کننده: RR: 0.94؛ 95% CI؛ 0.84 تا 1.06)، و انفارکتوس میوکارد (3 مطالعه، 4047 شرکت‌کننده: RR: 0.87؛ 95% CI؛ 0.71 تا 1.07)؛ و تاثیرات نامشخص بر سکته مغزی (2 مطالعه، 4018 شرکت‌کننده: RR: 1.29؛ 95% CI؛ 0.96 تا 1.72) داشتند.

خطرات عوارض جانبی ناشی از درمان با استاتین نامشخص بود؛ که شامل تاثیرات بر افزایش کراتین‌کیناز (5 مطالعه، 3067 شرکت‌کننده: RR: 1.25؛ 95% CI؛ 0.55 تا 2.83) یا آنزیم‌های عملکرد کبد (4 مطالعه، 3044 شرکت‌کننده؛ RR: 1.09؛ 95% CI؛ 0.41 تا 1.25)، ترک مطالعه به دلیل عوارض جانبی (9 مطالعه، 1832 شرکت‌کننده: RR: 1.04؛ 95% CI؛ 0.87 تا 1.25) یا سرطان (2 مطالعه، 4012 شرکت‌کننده: RR: 0.90؛ 95% CI؛ 0.72 تا 1.11) بودند. استاتین‌ها کلسترول تام سرم (14 مطالعه، 1803 شرکت‌کننده؛ MD؛ 44.86‐ میلی‌گرم/دسی‌لیتر؛ 95% CI؛ 55.19‐ تا 34.53‐) و کلسترول لیپوپروتئین با چگالی پائین (12 مطالعه، 1747 شرکت‌کننده: MD؛ 39.99‐ میلی‌گرم/دسی‌لیتر؛ 95% CI؛ 52.46‐ تا 27.52) را کاهش دادند. داده‌های مقایسه مستقیم درمان با استاتین با استاتین دیگر پراکنده بودند.

نتیجه‌گیری‌های نویسندگان

استاتین‌ها تاثیرات مفید اندک یا عدم تاثیر بر مرگ‌ومیر یا حوادث قلبی عروقی و عوارض جانبی نامطمئن در بزرگسالان تحت درمان دیالیز دارند، علیرغم اینکه کاهش مرتبط بالینی در سطح کلسترول سرم دیده شد.

خلاصه به زبان ساده

آیا درمان با استاتین باعث بهبود بقا یا کاهش خطر بیماری قلبی در افراد تحت دیالیز می‌شود؟

بزرگسالان مبتلا به بیماری شدید کلیوی که تحت درمان دیالیز قرار دارند، در معرض خطر بالای ابتلا به بیماری قلبی هستند. درمان با استاتین خطرات مرگ‌ومیر و عوارض بیماری قلبی را در جمعیت عمومی کاهش می‌دهد.

در سال 2009، تعداد 14 مطالعه را شناسایی کردیم که 2086 بیمار را وارد کردند، و دریافتیم در حالی که استاتین‌ها عموما بی‌خطر هستند و سطح کلسترول را کاهش می‌دهند، از وقوع مرگ یا حوادث قلبی بالینی در افرادی که تحت درمان دیالیز قرار دارند، پیشگیری نمی‌کنند. این آخرین به‌روزرسانی، در مجموع 25 مطالعه (8289 بیمار) را آنالیز کرد، و شامل نتایج حاصل از دو مطالعه بزرگ جدید بود. ما دریافتیم که استاتین‌ها کلسترول را در افرادی که تحت درمان دیالیز قرار دارند کاهش می‌دهد اما از وقوع مرگ‌ومیر، حمله قلبی، یا سکته مغزی پیشگیری نمی‌کند.

شواهد برای عوارض جانبی ناقص بود، و مضرات بالقوه درمان با استاتین نامشخص باقی ماند. داده‌های مطالعه کنونی نشان ندادند که درمان با استاتین باید با شروع دیالیز متوقف شود یا خیر، اگرچه مزایای مرتبط با ادامه درمان احتمالا اندک است. اطلاعات محدودی برای افراد تحت درمان با دیالیز صفاقی در دسترس بود که نشان می‌دهد انجام تحقیقات بیشتری در این زمینه مورد نیاز است.

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.

Summary of findings

Open in table viewer
Summary of findings for the main comparison.

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk/year/1000 treated

Corresponding risk/year/1000 treated

Placebo or no treatment

Statin

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

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)

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 Table 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.


Study selection flow diagram

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 2002Saltissi 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.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies


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

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 2002Saltissi 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 2002Saltissi 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 2002Saltissi 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 2002Saltissi 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 Table 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 Table 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 2002Saltissi 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 2002Saltissi 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 2002Saltissi 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.

Study selection flow diagram
Figuras y tablas -
Figure 1

Study selection flow diagram

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies
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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

Risk of bias summary: review authors' judgements about each risk of bias item for each included study
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Figure 3

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

Comparison 1 Statin versus placebo or no treatment, Outcome 1 Major cardiovascular events.
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Analysis 1.1

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

Comparison 1 Statin versus placebo or no treatment, Outcome 2 All‐cause mortality.
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Analysis 1.2

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

Comparison 1 Statin versus placebo or no treatment, Outcome 3 Cardiovascular mortality.
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Analysis 1.3

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

Comparison 1 Statin versus placebo or no treatment, Outcome 4 Fatal and non‐fatal myocardial infarction.
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Analysis 1.4

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

Comparison 1 Statin versus placebo or no treatment, Outcome 5 Fatal and non‐fatal stroke.
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Analysis 1.5

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

Comparison 1 Statin versus placebo or no treatment, Outcome 6 Elevated creatine kinase.
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Analysis 1.6

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

Comparison 1 Statin versus placebo or no treatment, Outcome 7 Elevated liver function enzymes.
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Analysis 1.7

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

Comparison 1 Statin versus placebo or no treatment, Outcome 8 Withdrawal due to adverse events.
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Analysis 1.8

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

Comparison 1 Statin versus placebo or no treatment, Outcome 9 Cancer.
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Analysis 1.9

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

Comparison 1 Statin versus placebo or no treatment, Outcome 10 Total cholesterol.
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Analysis 1.10

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

Comparison 1 Statin versus placebo or no treatment, Outcome 11 LDL cholesterol.
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Analysis 1.11

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

Comparison 1 Statin versus placebo or no treatment, Outcome 12 Triglycerides.
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Analysis 1.12

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

Comparison 1 Statin versus placebo or no treatment, Outcome 13 HDL cholesterol.
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Analysis 1.13

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

Comparison 2 Statin versus another statin, Outcome 1 Elevated liver function enzymes.
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Analysis 2.1

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

Comparison 2 Statin versus another statin, Outcome 2 Withdrawal due to adverse events.
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Analysis 2.2

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

Comparison 2 Statin versus another statin, Outcome 3 Total cholesterol.
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Analysis 2.3

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

Comparison 2 Statin versus another statin, Outcome 4 LDL cholesterol.
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Analysis 2.4

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

Comparison 2 Statin versus another statin, Outcome 5 Triglycerides.
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Analysis 2.5

Comparison 2 Statin versus another statin, Outcome 5 Triglycerides.

Comparison 2 Statin versus another statin, Outcome 6 HDL cholesterol.
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Analysis 2.6

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

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

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk/year/1000 treated

Corresponding risk/year/1000 treated

Placebo or no treatment

Statin

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

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)

Figuras y tablas -
Comparison 1. Statin versus placebo or no treatment

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Major cardiovascular events Show forest plot

4

7084

Risk Ratio (IV, Random, 95% CI)

0.95 [0.88, 1.03]

2 All‐cause mortality Show forest plot

13

4705

Risk Ratio (IV, Random, 95% CI)

0.96 [0.90, 1.02]

3 Cardiovascular mortality Show forest plot

13

4627

Risk Ratio (IV, Random, 95% CI)

0.94 [0.84, 1.06]

4 Fatal and non‐fatal myocardial infarction Show forest plot

3

4047

Risk Ratio (IV, Random, 95% CI)

0.87 [0.71, 1.07]

5 Fatal and non‐fatal stroke Show forest plot

2

4018

Risk Ratio (IV, Random, 95% CI)

1.29 [0.96, 1.72]

6 Elevated creatine kinase Show forest plot

5

3067

Risk Ratio (IV, Random, 95% CI)

1.25 [0.55, 2.83]

7 Elevated liver function enzymes Show forest plot

4

3044

Risk Ratio (IV, Random, 95% CI)

1.09 [0.41, 2.91]

8 Withdrawal due to adverse events Show forest plot

9

1832

Risk Ratio (IV, Random, 95% CI)

1.04 [0.87, 1.25]

9 Cancer Show forest plot

2

4012

Risk Ratio (IV, Random, 95% CI)

0.90 [0.72, 1.11]

10 Total cholesterol Show forest plot

14

1803

Mean Difference (IV, Random, 95% CI)

‐44.86 [‐55.19, ‐34.53]

11 LDL cholesterol Show forest plot

12

1747

Mean Difference (IV, Random, 95% CI)

‐39.99 [‐52.46, ‐27.52]

12 Triglycerides Show forest plot

13

1692

Mean Difference (IV, Random, 95% CI)

‐18.02 [‐31.00, ‐3.04]

13 HDL cholesterol Show forest plot

13

1769

Mean Difference (IV, Random, 95% CI)

2.57 [‐0.39, 5.52]

Figuras y tablas -
Comparison 1. Statin versus placebo or no treatment
Comparison 2. Statin versus another statin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Elevated liver function enzymes Show forest plot

1

Risk Ratio (IV, Random, 95% CI)

Totals not selected

2 Withdrawal due to adverse events Show forest plot

1

Risk Ratio (IV, Random, 95% CI)

Totals not selected

3 Total cholesterol Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

4 LDL cholesterol Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

5 Triglycerides Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

6 HDL cholesterol Show forest plot

1

Mean Difference (IV, Random, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 2. Statin versus another statin