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HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass

  1. Michelle Lewicki1,*,
  2. Irene Ng2,
  3. Antoine G Schneider1

Editorial Group: Cochrane Renal Group

Published Online: 30 APR 2013

DOI: 10.1002/14651858.CD010480


How to Cite

Lewicki M, Ng I, Schneider AG. HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD010480. DOI: 10.1002/14651858.CD010480.

Author Information

  1. 1

    Monash University, Department of Epidemiology and Preventive Medicine, Melbourne, VIC, Australia

  2. 2

    Royal Melbourne Hospital, Department of Anaesthesia and Pain Management, Parkville, VIC, Australia

*Michelle Lewicki, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia. michellelewicki@me.com.

Publication History

  1. Publication Status: New
  2. Published Online: 30 APR 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

Acute kidney injury (AKI) is a common complication of cardiac surgery with an incidence ranging from 1% to 30% according to the definition used (Conlon 1999; Mariscalco 2011; Ostermann 2000; Thakar 2003). Cardiac surgery-associated AKI (csa-AKI) has been shown to be independently associated with increased morbidity and mortality (Chertow 1997) and a more complicated hospital course. It is associated with longer stay in ICU and increased costs in particular when renal replacement therapy (RRT) is required (Coca 2009; Srisawat 2010; Swaminathan 2007). The use of cardiopulmonary bypass has been identified as an important risk factor for the occurrence of csa-AKI (Bove 2004; Chawla 2012; Lamy 2012), and the morbidity and mortality associated with development of this condition has not changed over the last decade despite significant technological advances in bypass technology (Swaminathan 2007). Further identified risk factors for development of AKI post cardio-pulmonary bypass include pre-existing chronic kidney disease (CKD) (Chertow 1997); older age (Mangano 1998); female gender (Asimakopoulos 2005); reduced left ventricular function (Mistiaen 2009); congestive heart failure (Mangano 1998); diabetes mellitus (Chukwuemeka 2005); peripheral vascular disease (Chukwuemeka 2005); preoperative use of an intra-aortic balloon pump (Bove 2004); need for emergent surgery (Bove 2004); pre-existing anaemia (Karkouti 2009); cardiopulmonary bypass (CPB) time (Bove 2004); duration of cross clamp time (Mistiaen 2009); and requirement of vasopressor support (Arora 2008).

While an overall decrease in renal blood flow has been shown to significantly contribute to the diminished glomerular filtration rate (GFR) observed in ischaemic renal injury, the decrease in renal blood flow alone cannot account for the total reduction in GFR. Renal toxicity is also thought to be mediated by cardiopulmonary bypass triggered activation of bone marrow derived cells, endothelial cells and renal epithelial cells resulting in reactive oxygen species generation and release of inflammatory mediators (Boyle 1997; Chello 2003). The adhesion of such inflammatory cells to activated endothelium in peritubular capillaries of the outer medulla leads to medullary congestion and hypoxic injury to the proximal tubule. Pro-inflammatory cytokines secreted by infiltrating and resident cells contribute to further tissue injury until inflammatory resolution and tubular epithelial proliferation occurs bringing a return to normal tissue function (Devarajan 2006).

 

Description of the intervention

Statins competitively inhibit the enzyme 3-hydroxy 3-methylglutaryl CoA reductase which catalyses the rate limiting step in cholesterol synthesis (Endo 1976). Since approval for clinical use in 1987 statins have been shown to reduce the progression of atherosclerosis, improve survival and reduce the risks of vascular death, non-fatal myocardial infarction (MI), stroke, and the need for coronary revascularisation across a wide range of cholesterol levels (Baigent 2005).

 

How the intervention might work

HMG CoA reductase inhibitors (statins) in addition to their lipid lowering actions have been shown to have anti-inflammatory and pleiotropic effects (Haslinger-Löffler 2008). In experimental models of AKI (Gueler 2002; Inman 2005; Yokota 2003), statins have been shown to preserve renal function. Similarly, some studies (Mariscalco 2011) have suggested that statins could reduce postoperative leukocyte and endothelial activation and result in significantly lower postoperative pro-inflammatory serum cytokine levels. There are some evidence that statin administration before percutaneous coronary interventions reduces periprocedural cardiovascular events. However, results are more conflicting when AKI (then called contrast-induced nephropathy) is considered as an outcome (Jo 2008; Ozan 2010; Patti 2008). A recent meta-analysis (Li 2012) supported the use of statins but concluded that their use must be considered in the context of variable patient demographics. In patients undergoing cardiac surgery, results are conflicting and only small randomised control trials (RCT) have been published to date.

 

Why it is important to do this review

In the absence of a large RCT, current evidence relies on numerous observational trials with conflicting results and a few small RCT's. Although several systematic reviews have evaluated the overall benefits of perioperative statins in cardiac surgery (Liakopoulos 2008; Liakopoulos 2012), none of them have focused on AKI as a primary outcome. We propose a more specific review focusing on AKI with a search strategy as outlined including procedures requiring cardiac bypass, with the exception of cardiac transplantation surgery and correction of congenital cardiac disease. All levels of renal injury will be included. There is a considerable need for effective therapies that prevent AKI in this setting as renal dysfunction after surgery results in significantly increased morbidity compared with those who have maintained normal renal function (Karkouti 2009). In general prevention of renal reperfusion injury after cardiac bypass surgery involves correction of dehydration and minimising nephrotoxins. Therefore the evidence showing that statins help prevent renal injury in this setting will help fill this therapeutic gap. Recent evidence (even amongst those patients not requiring RRT following AKI) suggests that renal injury was associated with increased long-term mortality risk independent of residual renal function, with risk proportionate to the severity of the renal injury (Lafrance 2010). The purpose of this review is to examine the evidence that suggests that statins may prevent AKI in patients undergoing surgery requiring cardiac bypass.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

This review aims to look at the evidence that supports the benefits of perioperative statins in prevention of AKI occurring in hospitalised adults after surgery requiring cardiac bypass. The main objectives are:

  1. To determine whether statin use is associated with the prevention of development of AKI.
  2. To determine whether the use of statins is associated with a reduction in in-hospital mortality.
  3. To determine whether the use of statins is associated with a reduction in the need for renal replacement therapy.
  4. To determine any adverse effects associated with the use of statins.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

All published randomised controlled trials (RCTs) that compare the use of statin to placebo or standard treatment given pre-operatively to patients having surgery requiring cardiac bypass. The dose, type or duration of statins used are not restricted. Only published trials are included, no abstract presentations will be included. Case reports and non-randomised studies will not be included in the review.

 

Types of participants

 

Inclusion criteria

All adult patients (age > 18 years) who undergo surgery requiring cardiac bypass will be included. Trials including paediatric subjects or mixed paediatric and adult populations will be excluded.

 

Exclusion criteria

  1. Patients on extracorporeal RRT prior to the initiation of the study.
  2. Patients undergoing cardiac transplantation or corrective surgery for congenital heart disease.
  3. Kidney transplant recipients.

 

Types of interventions

RCT's assessing the use of statin therapy for any given duration and dose prior to surgery requiring cardiac bypass compared to placebo, or no drug therapy or standard clinical care. All statins will be considered for inclusion, with a priori subgroup analysis defined.

 

Types of outcome measures

 

Primary outcomes

The primary outcome is the incidence of AKI after cardiac surgery. AKI will be defined using the AKIN or RIFLE classification wherever provided. The Acute Kidney Injury Network (AKIN) (Mehta 2007) defines three stages of injury (1, 2 and 3) based on increasingly severe reductions of kidney function (Stage 1: increase in serum creatinine ≥ 0.3 mg/dL, or 1.5- to 2-fold increase from baseline; Stage 2: increase in serum creatinine ≥ 150% to 200% from baseline; Stage 3: increase in serum creatinine > 3-fold from baseline, > 300% from baseline, ≥ 4.0 mg/dL, or initiation of RRT regardless of stage). The RIFLE criteria, proposed by the AQDI (Acute Dialysis Quality Initiative) group (Bellomo 2004) defines five levels of AKI (risk, injury, failure, loss and end-stage kidney disease) again based on incremental reductions in kidney function. If AKI is not reported in the context of these criteria, efforts will be made to classify patients according to these criteria. If necessary, authors will be contacted to provide additional data surrounding creatinine and urine output (if available) to enable this conversion.

 

Secondary outcomes

  1. Serum creatinine changes during the same hospitalisation
  2. In-hospital mortality.
  3. Need for RRT during the same hospitalisation.
  4. Adverse effects attributed to the intervention (elevated liver enzymes, creatinine kinase levels, rhabdomyolysis or withdrawal of drug)

 

Search methods for identification of studies

 

Electronic searches

We will search the Cochrane Renal Group's Specialised Register 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:

  1. Monthly searches of the Cochrane Central Register of Controlled Trials CENTRAL;
  2. Weekly searches of MEDLINE OVID SP;
  3. Handsearching of renal-related journals & 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 & 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 nephrology textbooks, review articles and relevant studies.
  2. Letters seeking information about unpublished or incomplete trials to investigators known to be involved in previous studies.

 

Searching other resources

For completion, assessment of potential trials in progress, or awaiting publication will be sought through searches of ClinicalTrials.gov (www.clinicaltrials.gov). Further potential trials will be assessed through hand-searching reference lists of included trials. Letters seeking information about unpublished or incomplete studies will be sent to investigators known to be involved in those studies.

 

Data collection and analysis

 

Selection of studies

Literature search will be performed using a predefined search strategy (see Appendix 1). The titles and abstracts will be screened initially. Studies that potentially contained information relevant to the review will be retained, whereas studies that do not meet the pre-specified criteria will be discarded. All three authors will independently review and select studies from EMBASE, CENTRAL and MEDLINE database. All of the potentially relevant studies will then be uploaded to a reference management software database (Review Manager 5). Each author will then review the full text of the retained articles to assess suitability for inclusion of the study. Reasons for exclusion will be noted. Crosscheck will be performed among all three authors to determine the final eligibility for inclusion. Disagreement will be arbitrated until a consensus is reached.

 

Data extraction and management

Data will be extracted independently by all three authors using a data extraction form, which will be designed by AS and piloted by all three authors. The information obtained will be cross-checked by each author. Disagreement will be arbitrated until a consensus is reached. Where more than one publication of a study exists, reports will be grouped together and the most complete data set will be included. Any discrepancy between published versions will be highlighted. The following data will be extracted:

 

Study characteristics

  • Study design
  • Country of the study performed
  • Number of centres involved
  • Inclusion criteria
  • Exclusion criteria
  • Total number of included patients in both treatment group and placebo group

 

Patient characteristics

  • Age, sex, baseline CKD, diabetes, hypertension, chronic statin use, elective or emergency surgery

 

Interventions and outcomes

  • Statin regimen including the type of statins, the dose and duration
  • Proportion with AKI
  • Proportion requiring RRT
  • Mortality rate
  • Proportion with adverse events
  • Pre and postoperative serum creatinine level
  • Any other outcomes collected for the study

 

Other Information

  • Source of funding
  • Any other relevant information

Attempts will be made to retrieve any missing data or information through direct correspondence with the primary author of the relevant study.

 

Assessment of risk of bias in included studies

All three authors will perform the risk of bias assessment for all of the included studies according to the standards of the Cochrane Collaboration (Higgins 2011)(see 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?

Studies will be labelled “low risk of bias”, “high risk of bias” or “unclear risk of bias” with reasons documented and a “risk of bias summary” will be presented. Studies with high risk of bias will be identified and this will be taken into account in the outcome analysis.

 

Measures of treatment effect

For dichotomous outcomes (e.g. proportion of AKI, need for RRT, mortality rates and number of adverse events), results will be expressed as risk ratios (RR) with 95% confidence intervals (CI). A RR < 1 favours statin treatment over control. As postoperative serum creatinine is a continuous outcome it will be first converted to standardised units (µmol/L) and the mean difference (MD) with 95% CI will subsequently be used for comparison.

 

Unit of analysis issues

Studies with non-standard designs, such as cross-over trials and cluster-randomised trials will not be included in this review.

 

Dealing with missing data

Any further information required from the original author will be requested by written correspondence and any relevant information obtained in this manner will be included in the review.

 

Assessment of heterogeneity

We will assess the heterogeneity between included studies using the Chi² test on N-1 degrees of freedom with an alpha of 0.05 used for statistical significance and with the I² statistic (Higgins 2003). We consider statistical significance in heterogeneity surrounding calculation of the I², although Chi² with alpha < 0.05 will also be considered. Based on the Cochrane Handbook (Higgins 2011), I² of 0% to 40% may not be important, I² of 30% to 60% may represent moderate heterogeneity, I² of 50% to 90% may represent substantial heterogeneity and I² of 75% to 100% may represent considerable heterogeneity. Visual inspection of forest plots will provide added evidence of heterogeneity.

 

Assessment of reporting biases

In order to detect any publication bias, electronic searching of websites with current clinical trial protocols will be undertaken. Funnel plot analysis (Sterne 2001) is planned to further investigate publication bias if there is sufficient number of included studies. Language bias is minimized by not applying any language restrictions during the search strategy.

 

Data synthesis

The data from the available randomised controlled trials will be pooled using the random effects model (DerSimonian 1986), however the fixed effects model (Egger 1997) will also be undertaken to ensure the robustness of the model and susceptibility to outliers. The random effects model is to be used for the primary analysis as there may be variability in the form, dose and duration of statin therapy used amongst trials of this nature, and some heterogeneity may be expected. Before a pooled data analysis is performed for each outcome of interest, the authors will assess all the relevant studies to determine the eligibility of data comparison. Results will be presented within the narrative if there are not sufficient comparable data available to undertake a pooled analysis for a specific outcome.

 

Subgroup analysis and investigation of heterogeneity

Subgroup analysis will be used to explore possible sources of heterogeneity such as those amongst participants, treatments and study quality. Heterogeneity in patients could be related to age, preoperative renal pathology and other risk factors for renal reperfusion injury. Heterogeneity in treatments could be related to prior agent(s) used and the dose, duration and type of statin used. If sufficient studies are identified we will investigate these potential differences.

 

Sensitivity analysis

We will perform sensitivity analyses if there are sufficient studies identified, in order to explore the influence of the following factors on effect size:

  • repeating the analysis excluding unpublished studies;
  • repeating the analysis taking account of risk of bias, as specified above;
  • repeating the analysis excluding any very long or large studies to establish how much they dominate the results;
  • repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

  • We are grateful to the Cochrane Renal Group for assistance in preparation of this manuscript
  • We also wish to thank the team in the Department of Epidemiology and Preventative Medicine at Monash University, particularly Renea Johnston and Rachelle Buchbinder for their help in preparation of this manuscript
  • We also thank Adam Clark for assistance with development of the search strategies

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. Electronic search strategies


DatabaseSearch terms

CENTRAL
  1. MeSH descriptor: [Coronary Artery Bypass] explode all trees
  2. bypass*:ti,ab,kw in Trials
  3. coronary artery bypass*:ti,ab,kw in Trials
  4. coronary bypass grafting surgery:ti,ab,kw in Trials
  5. (valve* or cardiac) and surger*:ti,ab,kw in Trials
  6. CABG:ti,ab,kw in Trials
  7. MeSH descriptor: [Thoracic Surgery] this term only
  8. cardiac surg*:ti,ab,kw in Trials
  9. valve replacement*:ti,ab,kw in Trials
  10. #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 in Trials
  11. MeSH descriptor: [Hydroxymethylglutaryl-CoA Reductase Inhibitors] explode all trees
  12. statin*:ti,ab,kw in Trials
  13. "HMG-CoA":ti,ab,kw in Trials
  14. hydroxymethylglutaryl-coa reductase inhibitor*:ti,ab,kw in Trials
  15. simvastatin:ti,ab,kw OR fluvastatin:ti,ab,kw OR cervistatin:ti,ab,kw OR lovastatin:ti,ab,kw OR pravastatin:ti,ab,kw in Trials
  16. atorvastatin:ti,ab,kw OR rosuvastatin:ti,ab,kw OR Lipitor:ti,ab,kw OR Baycol:ti,ab,kw OR Lescol:ti,ab,kw in Trials
  17. (Mevcor):ti,ab,kw or (Altocar):ti,ab,kw or (Pravacol):ti,ab,kw or (Lipostat):ti,ab,kw or (Zocor):ti,ab,kw or (Crestor):ti,ab,kw in Trials
  18. #11 or #12 or #13 or #14 or #15 or #16 or #17 in Trials
  19. MeSH descriptor: [Acute kidney Injury] explode all trees
  20. acute kidney failure*:ti,ab,kw OR acute renal failure*:ti,ab,kw in Trials
  21. acute kidney injur*:ti,ab,kw OR acute renal injur*:ti,ab,kw in Trials
  22. acute kidney insufficie*:ti,ab,kw OR acute renal insufficie*:ti,ab,kw in Trials
  23. acute tubular necrosis:ti,ab,kw in Trials
  24. ARF or AKF or ATN:ti,ab,kw in Trials
  25. #19 or #20 or #21 or #22 or #23 or #24 in Trials
  26. #10 and #18 in Trials
  27. #10 and #25 in Trials
  28. #18 and #25 in Trials
  29. #26 or #27 or #28 in Trials

MEDLINE1. exp Coronary Artery Bypass/

2. bypass.tw.

3. coronary artery bypass$.tw.

4. coronary bypass grafting surgery.tw.

5. ((valve$ or cardiac) and surgery).tw.

6. CABG.tw.

7. Thoracic Surgery/

8. cardiac surgery.tw.

9. valve replacement$.tw.

10. or/1-9

11. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/

12. statin$.tw. 13. "HMG-CoA".tw.

14. hydroxymethylglutaryl-coa reductase inhibitor$.tw.

15. simvastatin.tw.

16. fluvastatin.tw.

17. cervistatin.tw.

18. lovastatin.tw.

19. pravastatin.tw.

20. atorvastatin.tw.

21. rosuvastatin.tw.

22. Lipitor.tw.

23. Baycol.tw.

24. Lescol.tw.

25. Mevcor.tw.

26. Altocar.tw.

27. Pravacol.tw.

28. Lipostat.tw.

29. Zocor.tw.

30. Crestor.tw.

31. or/11-30

32. exp Acute Kidney Injury/

33. (acute kidney failure or acute renal failure).tw.

34. (acute kidney injur$ or acute renal injur$).tw.

35. (acute kidney insufficie$ or acute renal insufficie$).tw.

36. acute tubular necrosis.tw.

37. (ARF or AKF or ATN).tw.

38. or/32-37

39. and/10,31

40. and/10,38

41. and/31,38

42. or/39-41

EMBASE1. exp coronary artery surgery/

2. thorax surgery/

3. bypass.tw.

4. coronary artery bypass$.tw.

5. coronary bypass grafting surgery.tw.

6. ((valve$ or cardiac) and surgery).tw.

7. CABG.tw.

8. cardiac surgery.tw.

9. valve replacement$.tw.

10. or/1-9

11. exp hydroxymethylglutaryl coenzyme A reductase inhibitor/

12. statin$.tw.

13. "HMG-CoA".tw.

14. hydroxymethylglutaryl-coa reductase inhibitor$.tw.

15. (simvastatin or fluvastatin or cervistatin or lovastatin or pravastatin or atorvastatin or rosuvastatin).tw.

16. (Lipitor or Baycol or Lescol or Mevcor or Altocar or Pravacol or Lipostat or Zocor or Crestor).tw.

17. or/11-16

18. exp acute kidney failure/

19. (acute kidney failure or acute renal failure).tw.

20. (acute kidney injur$ or acute renal injur$).tw.

21. (acute kidney insufficie$ or acute renal insufficie$).tw.

22. acute tubular necrosis.tw.

23. (ARF or AKF or ATN).tw.

24. or/18-23

25. and/10,17

26. and/10,24

27. and/17,24

28. or/25-27



 

Appendix 2. Risk of bias assessment tool


Potential source of biasAssessment 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.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

  1. Draft the protocol: ML, AS, IN
  2. Study selection: ML, AS, IN
  3. Extract data from studies: ML, AS, IN
  4. Enter data into RevMan: AS
  5. Carry out the analysis: ML, AS, IN
  6. Interpret the analysis: ML
  7. Draft the final review: ML, AS, IN
  8. Disagreement resolution: ML, AS, IN
  9. Update the review: ML

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

None declared

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • No sources of support supplied

 

External sources

  • Dr M Lewicki, Australia.
    Supported through a Jacquot Research Entry Scholarship, RACP Foundation Australia
  • Dr A Schneider, Switzerland.
    Supported through a MGS-MIPRS Research Scholarship, Monash University Australia

References

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
Arora 2008
  • Arora P, Rajagopalam S, Ranjan R, Kolli H, Singh M, Venuto R, et al. Preoperative use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers is associated with increased risk for acute kidney injury after cardiovascular surgery. Clinical Journal of the American Society of Nephrology: CJASN 2008;3(5):1266-73. [MEDLINE: 18667735]
Asimakopoulos 2005
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