HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass
Abstract
Background
Acute kidney injury (AKI) is common in patients undergoing cardiac surgery among whom it is associated with poor outcomes, prolonged hospital stays and increased mortality. Statin drugs can produce more than one effect independent of their lipid lowering effect, and may improve kidney injury through inhibition of postoperative inflammatory responses.
Objectives
This review aimed to look at the evidence supporting the benefits of perioperative statins for AKI prevention in hospitalised adults after surgery who require cardiac bypass. The main objectives were to 1) determine whether use of statins was associated with preventing AKI development; 2) determine whether use of statins was associated with reductions in in‐hospital mortality; 3) determine whether use of statins was associated with reduced need for RRT; and 4) determine any adverse effects associated with the use of statins.
Search methods
We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co‐ordinator using search terms relevant to this review.
Selection criteria
Randomised controlled trials (RCTs) that compared administration of statin therapy with placebo or standard clinical care in adult patients undergoing surgery requiring cardiopulmonary bypass and reporting AKI, serum creatinine (SCr) or need for renal replacement therapy (RRT) as an outcome were eligible for inclusion. All forms and dosages of statins in conjunction with any duration of pre‐operative therapy were considered for inclusion in this review.
Data collection and analysis
All authors extracted data independently and assessments were cross‐checked by a second author. Likewise, assessment of study risk of bias was initially conducted by one author and then by a second author to ensure accuracy. Disagreements were arbitrated among authors until consensus was reached. Authors from two of the included studies provided additional data surrounding post‐operative SCr as well as need for RRT. Meta‐analyses were used to assess the outcomes of AKI, SCr and mortality rate. Data for the outcomes of RRT and adverse effects were not pooled. Adverse effects taken into account were those reported by the authors of included studies.
Main results
We included seven studies (662 participants) in this review. All except one study was assessed as being at high risk of bias. Three studies assessed atorvastatin, three assessed simvastatin and one investigated rosuvastatin. All studies collected data during the immediate perioperative period only; data collection to hospital discharge and postoperative biochemical data collection ranged from 24 hours to 7 days. Overall, pre‐operative statin treatment was not associated with a reduction in postoperative AKI, need for RRT, or mortality. Only two studies (195 participants) reported postoperative SCr level. In those studies, patients allocated to receive statins had lower postoperative SCr concentrations compared with those allocated to no drug treatment/placebo (MD 21.2 µmol/L, 95% CI ‐31.1 to ‐11.1). Adverse effects were adequately reported in only one study; no difference was found between the statin group compared to placebo.
Authors' conclusions
Analysis of currently available data did not suggest that preoperative statin use is associated with decreased incidence of AKI in adults after surgery who required cardiac bypass. Although a significant reduction in SCr was seen postoperatively in people treated with statins, this result was driven by results from a single study, where SCr was considered as a secondary outcome. The results of the meta‐analysis should be interpreted with caution; few studies were included in subgroup analyses, and significant differences in methodology exist among the included studies. Large high quality RCTs are required to establish the safety and efficacy of statins to prevent AKI after cardiac surgery.
PICOs
Plain language summary
Do statins prevent kidney failure in adults after surgery where cardiac bypass is used?
Heart surgeries are performed routinely in developed countries and their safety has increased significantly. However, heart surgery is still associated with complications. Of those, kidney failure is of great importance; and patients whose kidneys fail after a heart operation are more likely to have other health problems. Preventing kidney failure after heart surgery is therefore a major health issue.
Cardiac bypass, which replaces heart and lung functions by diverting blood from major vessels to a machine during surgery, is required for most major heart operations. Cardiac bypass is known to release molecules that cause inflammation into the blood. In susceptible people, these molecules could cause kidney failure. Statins are drugs used to decrease fatty acid (lipid) levels in the blood and help prevent cardiac and vascular disease. Statins also seem to decrease the general level of inflammation in the blood. Although animal studies have suggested that statins could help to prevent kidney failure after heart surgery, they can also cause adverse effects. More evidence is required before statins can be routinely used.
This review aims to evaluate evidence on the use of statins at the time of heart surgery to investigate if use can help to prevent kidney failure and how well statins are tolerated among patients. We searched the literature to January 2015 and included seven studies that involved a total of 662 participants to inform our assessment. In these studies, patients planned for heart surgery received statins or placebo (or no treatment at all). Five studies (467 participants) reported rates of kidney failure. We found that there was a high risk of bias in six of the seven included studies.
We found no difference in the rate of kidney failure between patients who received statins and those who did not. Two studies (195 patients) reported serum creatinine (a marker of kidney function) after the operation. We found that serum creatinine was lower in patients in the statin group (indicating better kidney function). Other conclusions were limited by the small number of studies. However, patients who received statins did not seem to need less dialysis. They did not have a higher rate of death in hospital and did not have an increased rate of adverse events.
Authors' conclusions
Summary of findings
| Statin therapy compared with placebo for reduction in AKI after cardiac surgery with bypass | ||||||
| Patient or population: adults undergoing surgery requiring cardiac bypass Settings: hospital inpatients Intervention: statin treatment prior to cardiac bypass surgery Comparison: placebo or no drug therapy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo or no drug therapy | Statins | |||||
| Acute kidney injury Follow‐up: ICU stay | 27/232 (11.6%) | 21/235 (8.9%) | RR 0.76 (0.46 to 1.28) | 467 (5) | ⊕⊕⊝⊝ | No significant difference. High risk of bias in most studies |
| Serum creatinine Follow‐up: first 72 h post‐operative | The mean serum creatinine ranged across control groups from 77.6 to 106 µmol/L | The mean serum creatinine in intervention groups was on average 21 µmol/L lower (95% CI ‐31.09 to ‐11.41) | 195 (2) | ⊕⊕⊝⊝ | Significant difference, both studies have high risk of bias | |
| Renal replacement therapy Follow‐up: ICU stay | 5/124 (4.0%) | 4/127 (3.1%) | RR 0.8 (0.23 to 2.81) | 251 (2) | ⊕⊝⊝⊝ | No significant difference. Only one study reported the need for renal replacement therapy |
| Mortality Follow‐up: hospital stay | 0/189 (0%) | 3/192 (1.6%) | RR 3.86 (0.43 to 34.4) | 381 (5) | ⊕⊝⊝⊝ | No significant difference. Very low event rate. High risk of bias amongst studies |
| Adverse events Follow‐up: treatment duration | 8/70 (11.4%) | 9/70 (12.9%) | RR 1.13 (1.47 to 2.68) | 140 (1) | ⊕⊝⊝⊝ | No significant difference. Only one study adequately reported adverse events |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ICU ‐ intensive care unit | ||||||
Background
Description of the condition
AKI is a common complication of cardiac surgery; incidence ranges 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 course of hospital admission. AKI is associated with longer intensive care unit (ICU) stays and increased costs, especially when renal replacement therapy (RRT) is required (Coca 2009; Srisawat 2010; Swaminathan 2007).
Cardiopulmonary bypass use has been identified as an important risk factor for occurrence of csa‐AKI (Bove 2004; Chawla 2012; Lamy 2012), and morbidity and mortality has not changed over the last decade despite significant advances in bypass technology (Swaminathan 2007). Other risk factors for development of AKI post cardiopulmonary 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), pre‐operative use of an intra‐aortic balloon pump (Bove 2004), need for emergent surgery (Bove 2004), pre‐existing anaemia (Karkouti 2009), cardiopulmonary bypass time (Bove 2004), duration of cross clamp time (Mistiaen 2009) and requirement for vasopressor support (Arora 2008).
Although an overall decrease in renal blood flow has been shown to significantly contribute to the diminished glomerular filtration rate (GFR) observed in ischaemic kidney injury, decreased 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). The adhesion of 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 (HMG 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, stroke, and the need for coronary revascularisation across a wide range of cholesterol levels (Baigent 2005).
How the intervention might work
In addition to their lipid lowering actions, statins have been shown to exert 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 kidney function. Similarly, Mariscalco 2011 suggested that statins could reduce postoperative leukocyte and endothelial activation and result in significantly lower postoperative pro‐inflammatory serum cytokine levels.
There is some evidence that statin administration before percutaneous coronary interventions reduces periprocedural cardiovascular events. However, results are inconsistent when AKI (contrast‐induced nephropathy) was considered as an outcome (Jo 2008; Ozan 2010; Patti 2008). A recent meta‐analysis (Li 2012) supported the use of statins to prevent contrast‐induced nephropathy but concluded that their use must be considered in the context of variable patient demographics. Although the pathophysiology of contrast‐induced nephropathy is not fully understood, inflammation and oxidative stress may play an important role similar to a postulated mechanism of kidney injury after cardiac bypass surgery. Only small RCTs have been published to date, and results among patients undergoing cardiac surgery are conflicting.
Why it is important to do this review
Current evidence consists of numerous observational studies and a few small RCTs. Large observational studies have generated conflicting results: some suggest that statin administration could be associated with lower csa‐AKI incidence (Billings 2010; Clark 2006; Tabata 2007) but others have suggested no effect (Ali 2005; Pan 2004). Given their retrospective nature, such studies are limited by selection bias and their conclusions must be considered with care. Several systematic reviews have evaluated the overall benefits of perioperative statins in cardiac surgery (Liakopoulos 2008; Liakopoulos 2012); however, none have focused on AKI as a primary outcome.
There is a considerable need for effective therapies that prevent AKI in this setting because kidney dysfunction after surgery results in significantly increased morbidity compared with patients who maintain normal kidney function (Karkouti 2009). In general, prevention of kidney reperfusion injury after cardiac bypass surgery involves correction of dehydration and minimising nephrotoxins. Therefore, evidence indicating that statins help to prevent kidney injury in this setting will help to address this therapeutic gap. Recent evidence (including among patients not requiring RRT following AKI) suggests that kidney injury is associated with increased long‐term mortality risk independent of residual kidney function, with risk proportionate to the severity of the kidney injury (Lafrance 2010).
This review focused on AKI and procedures requiring cardiac bypass, except cardiac transplantation surgery and correction of congenital cardiac defects. All levels of kidney injury were included.
Objectives
This review aimed to look at the evidence supporting the benefits of perioperative statins for AKI prevention in hospitalised adults after surgery who require cardiac bypass. The main objectives were:
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To determine whether use of statins was associated with preventing AKI development
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To determine whether use of statins was associated with reductions in in‐hospital mortality
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To determine whether use of statins was associated with reduced need for RRT
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To determine any adverse effects associated with the use of statins.
Methods
Criteria for considering studies for this review
Types of studies
All published RCTs that compared statin use with placebo or standard treatment given preoperatively to patients undergoing surgery who required cardiac bypass were eligible for inclusion. The dose, type or duration of statins used was not restricted. Case reports and non‐randomised studies were not eligible for inclusion.
Types of participants
Inclusion criteria
All adult patients (aged > 18 years) undergoing surgery requiring cardiopulmonary bypass were included. Studies including children or mixed child and adult populations were excluded unless data were presented separately. Studies that included patients undergoing cardiac surgery who did not require cardiopulmonary bypass were excluded.
Exclusion criteria
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Patients on extracorporeal RRT before the initiation of the study
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Patients undergoing cardiac transplantation or corrective surgery for congenital heart disease
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Kidney transplant recipients.
Types of interventions
We considered studies that investigated the use of statin therapy for any given duration and dose prior to surgery in people requiring cardiac bypass compared with placebo, no drug therapy or standard clinical care. All statins were 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 is 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 (SCr) ≥ 0.3 mg/dL, or 1.5‐ to 2‐fold increase from baseline; Stage 2: increase in SCr ≥ 150% to 200% from baseline; Stage 3: increase in SCr > 3‐fold from baseline, > 300% from baseline, ≥ 4.0 mg/dL, or initiation of RRT regardless of stage). The RIFLE criteria, proposed by the Acute Dialysis Quality Initiative group (Bellomo 2004) defines five levels of AKI (Risk, Injury, Failure, Loss and End‐stage kidney disease) based on incremental reductions in kidney function.
If AKI was not reported in the context of these criteria, efforts were made to classify patients.
Secondary outcomes
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SCr changes during the same hospitalisation
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In‐hospital mortality
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Need for RRT during the same hospitalisation
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Adverse effects attributed to the intervention (elevated liver enzymes, creatinine kinase levels, rhabdomyolysis or drug withdrawal).
Search methods for identification of studies
Electronic searches
We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 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.
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Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)
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Weekly searches of MEDLINE OVID SP
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Handsearching of renal‐related journals and the proceedings of major renal conferences
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Searching of the current year of EMBASE OVID SP
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Weekly current awareness alerts for selected renal journals
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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
Further potential studies were assessed through handsearching reference lists of nephrology textbooks, review articles and relevant studies. Letters were submitted seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.
Data collection and analysis
Selection of studies
Literature search was performed using the predefined search strategy (Appendix 1) to identify studies eligible for inclusion. The titles and abstracts were screened initially. Studies that potentially contained information relevant to the review were retained, whereas studies that did not meet the pre‐specified criteria were excluded. All potentially relevant studies were then uploaded to a reference management database. Each author independently reviewed the abstract or full text (where required) of the retained articles to assess suitability for inclusion in this review. Reasons for exclusion were noted. Cross checking was performed by at least one further author to determine the final eligibility for inclusion, and disagreements were arbitrated amongst all three authors until a consensus was reached.
Data extraction and management
Data were extracted independently by all three authors using a standardised data extraction form, which was designed by AS and initially piloted by all three authors. The information obtained from each included study was cross‐checked by at least one additional author. Disagreements were arbitrated between all three authors until a consensus was reached. Where more than one publication of a study existed, reports were grouped together and the most complete data set was included. Any discrepancy between published versions has been highlighted. Unclear data were clarified through correspondence with the study authors and any data obtained in this way were included in the review and analysis. Data extracted included study design, inclusion and exclusion criteria, patient numbers and characteristics. Treatment regimen and duration as well as duration of follow‐up were included. For outcomes of interest (AKI, SCr, mortality, need for RRT, adverse events), the raw data were extracted using mean, median and standard deviations for continuous outcomes, and event rate for dichotomous outcomes. Where data were collected at more than one time‐point, we extracted all data and analysed different time‐points for comparison.
Assessment of risk of bias in included studies
All three authors independently performed the risk of bias assessment for between two to three of the included studies, with each assessment cross‐checked by a second author. Any disagreements were arbitrated between all three authors until a consensus was reached. Risk of bias was assessed using a risk of bias assessment tool (see Appendix 2), and according to the standards of the Cochrane Collaboration (Higgins 2011). The following items were assessed.
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Was there adequate sequence generation (selection bias)?
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Was allocation adequately concealed (selection bias)?
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Was knowledge of the allocated interventions adequately prevented during the study (detection bias)?
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Participants and personnel
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Outcome assessors
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Were incomplete outcome data adequately addressed (attrition bias)?
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Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?
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Was the study apparently free of other problems that could put it at a risk of bias?
In each domain, studies were labelled as low, high or unclear risk of bias with consideration given to the presence or absence of sufficient information to make a determination. Reasons for assessment were documented (See Characteristics of included studies), and a risk of bias summary is presented.
Measures of treatment effect
For dichotomous outcomes (e.g. proportion of AKI, need for RRT, mortality rates and number of adverse events), results are expressed as risk ratios (RR) with 95% confidence intervals (CI), calculated using the random effects model. A RR < 1 favours statin treatment over control. As postoperative SCr is a continuous outcome it was first converted to standardised units (µmol/L) and the mean difference (MD) with 95% CI was subsequently used for comparisons.
Unit of analysis issues
Studies with non‐standard designs, such as cross‐over studies and cluster‐randomised studies were not included in this review.
Dealing with missing data
Any missing outcome data were requested from the corresponding author of the study. All the relevant information obtained via this method was included in this review. In one included study (Almansob 2012), there was lack of information surrounding SCr levels which were graphically presented. After written correspondence, the authors of this study provided mean and standard deviation of the SCr level and blood urea nitrogen (BUN) preoperatively, and at 24 hours, 48 hours and 72 hours postoperatively. Data surrounding need for RRT and mortality data were also provided. An author from Prowle 2012 was contacted for perioperative SCr data, which were also provided. No further missing outcome data were imputed for the purposes of this review. Given the universally short follow‐up periods of the included studies, loss to follow‐up was minimal. In one study that reported 15 patients dropped out (Prowle 2012), data within this study were analysed on intention‐to‐treat principle, followed by reanalysis on per‐protocol basis, in which no outcomes were materially affected. The intention‐to‐treat data from this study were used for the purposes of this review. In the only other study reporting significant drop outs (Almansob 2012), only those completing the study were included in the analysis, and study data were used as reported.
Assessment of heterogeneity
We assessed 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 considered statistical significance in heterogeneity surrounding calculation of the I2, although Chi2 with alpha < 0.05 was also 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 provided added evidence of heterogeneity.
Assessment of reporting biases
In order to detect any publication bias, electronic searching of web sites with current clinical study protocols was undertaken. Funnel plot analysis (Sterne 2001) was planned to further investigate, however there were insufficient number of included studies and this analysis was not feasible. We also assessed selective reporting of outcomes in the included studies. Language bias was minimized by not applying any language restrictions during the search strategy.
Data synthesis
The data from the available studies were pooled using the random effects model (DerSimonian 1986), however the fixed effects model (Egger 1997) was also undertaken for comparison. The random effects model was used for the primary analysis as there is variability in the form, dose and duration of statin therapy used amongst studies of this nature, and some heterogeneity was expected. Before a pooled data analysis was performed for each outcome of interest, we assessed all the relevant studies to determine the eligibility of data comparison. We excluded pooled data analysis and only presented the result with narrative description when there were not sufficient comparable data available for a specific outcome.
Subgroup analysis and investigation of heterogeneity
Subgroup analysis was 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. Despite small numbers of included studies, we investigated the potential differences through subgroup analysis according to type of statin used.
Sensitivity analysis
We planned to perform sensitivity analyses if there were sufficient studies identified, in order to explore the influence of the following factors on effect size.
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Repeating the analysis excluding unpublished studies
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Repeating the analysis taking account of risk of bias, as specified above
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Repeating the analysis excluding any very long or large studies to establish how much they dominate the results
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Repeating the analysis excluding studies using the following filters: diagnostic criteria, language of publication, source of funding (industry versus other), and country.
Too few studies were identified that met the inclusion criteria for this review, therefore sensitivity analyses were not undertaken.
Results
Description of studies
See Characteristics of included studies; Characteristics of excluded studies
Results of the search
We identified 89 records from the Cochrane Renal Group's Specialised Register (Figure 1); no studies were identified from searches of the reference lists of relevant review articles (Liakopoulos 2008; Morgan 2009). After screening titles, abstracts and the full text, 53 studies (71 records) were excluded and two ongoing studies were identified (NCT01547455; STATIN AKI 2011). Seven studies met our inclusion criteria (Almansob 2012; Chello 2006; Christenson 1999; Mannacio 2008; Prowle 2012; Tamayo 2009; Spadaccio 2010).
Study flow diagram.
Prior to publication of this review a final search of the Specialised Register identified five new potential studies and these will be assessed for inclusion in a future update of this review (de Oliveira 2012; Han 2013; Liu 2013; NAPLES II Study 2009; ROSA‐cIN Trial 2013).
Included studies
The seven studies included in our analyses were all RCTs and included a treatment arm of statin and comparator arm of no drug treatment or placebo. The studies included had variable primary outcomes, however all included at least one of the pre‐specified outcomes of interest for this review. Authors were contacted to provide data for SCr and urine output and additional information for SCr was gained from two of the included studies.
See Characteristics of included studies
Design
After evaluation, seven RCTs published between 1999 and 2012 were included in this review. All were published in English.
Sample size
Sample size varied from 40 (Christenson 1999) to 200 participants (Mannacio 2008) to provide data on a total of 662 adult patients undergoing cardiac surgery, of whom 334 received statin therapy and 328 received placebo or no drug therapy.
Setting
Five of the seven studies were undertaken in European centres, and one each in China and Australia. All were undertaken in inpatient hospital settings with follow‐up limited to inpatient hospital stays.
Participants
All studies evaluated adult inpatients undergoing cardiac bypass. One study exclusively enrolled patients undergoing non‐coronary artery surgery (Almansob 2012) compared to the other included studies that predominantly evaluated those undergoing coronary artery bypass surgery. Most studies excluded those with baseline kidney impairment (Chello 2006; Mannacio 2008; Prowle 2012; Spadaccio 2010; Tamayo 2009) although of note, there was no consensus amongst these studies on levels of kidney impairment that led to exclusion.
Interventions
Three studies evaluated atorvastatin (Prowle 2012; Spadaccio 2010; Chello 2006), three evaluated simvastatin (Almansob 2012; Christenson 1999; Tamayo 2009) and one study evaluated rosuvastatin (Mannacio 2008). All studies compared pre‐operative statin treatment to placebo or no drug treatment. Use of statins prior to enrolment was variable, with three studies (Almansob 2012;Christenson 1999Tamayo 2009) not reporting prior use. Two studies (Chello 2006; Spadaccio 2010) had a mandated statin‐free period of more than one year prior to enrolment, and two studies had much shorter statin‐free periods of a minimum 30 days (Mannacio 2008) and 24 hours (Prowle 2012) prior to enrolment.
Doses of statin used varied; atorvastatin ranged from 20 mg/d (Chello 2006; Spadaccio 2010) to 40 mg/d (Prowle 2012), simvastatin was 20 mg/d (Almansob 2012; Christenson 1999; Tamayo 2009) and rosuvastatin was 20 mg/d (Mannacio 2008). Of note, only Christenson 1999 titrated statin dose to lipid levels, with simvastatin increased to 40 mg two weeks prior to surgery if adequate lipid lowering had not been achieved.
Duration of preoperative statin therapy was also variable between the studies, with periods ranging from commencement on the day of operation (Prowle 2012) through to four weeks preoperatively (Christenson 1999). Three of the studies commenced therapy three weeks prior to surgery (Chello 2006; Spadaccio 2010; Tamayo 2009) and two studies commenced therapy between five to seven days preoperatively (Almansob 2012; Mannacio 2008). The period of postoperative statin therapy was not clarified in 5/7 studies (Chello 2006; Christenson 1999; Mannacio 2008; Spadaccio 2010; Tamayo 2009). In two studies the statin was continued for three days postoperatively (Prowle 2012) and recommenced on day two postoperatively for ongoing therapy (Almansob 2012).
Outcomes
With the exception of Prowle 2012 none of the studies listed AKI as a primary outcome. For our pre‐specified outcomes of interest, 5/7 studies reported AKI (Chello 2006; Prowle 2012; Christenson 1999; Spadaccio 2010; Mannacio 2008), 3/7 studies reported SCr (Almansob 2012; Prowle 2012; Tamayo 2009), 2/7 studies reported need for RRT (Almansob 2012; Prowle 2012), 5/7 reported mortality (Almansob 2012; Chello 2006;Prowle 2012; Spadaccio 2010; Tamayo 2009), and 2/7 studies reported adverse events (Chello 2006; Prowle 2012). Standardisation of outcome reporting for the outcomes of AKI, SCr and adverse events was a significant issue. The definitions of AKI ranged from using the validated RIFLE criteria (Prowle 2012), to using a single SCr cut‐off (Christenson 1999) or increase in SCr (Mannacio 2008) to providing no clarifying definition (Chello 2006; Spadaccio 2010). No conversion to AKIN criteria was able to be achieved. Units of measure of SCr were able to be freely converted to µmol/L, however time point reporting varied widely amongst studies. Almansob 2012 reported SCr data at 24, 48 and 72 hour time points, while for Tamayo 2009 the time‐point of SCr was unable to be clarified, although data collection was ceased at 48 hours. Prowle 2012 reported only peak SCr values, which were taken one to five days postoperatively. Finally, adverse events were defined clearly in one study (Prowle 2012) as alanine transferase (ALT) > 3 times the upper limit or normal (ULN), creatine kinase (CK) > 5000 IU/L, or study drug being stopped by the treating clinician. Chello 2006 reported only that no adverse events were experienced, without qualification.
Excluded studies
Overall, 53 studies were excluded after critical appraisal of title, abstract or full text (See Characteristics of excluded studies). One study did not fulfil the criteria for a RCT; 24 contained no outcome of interest, 25 were excluded as they did not use cardiac bypass in the procedure and three did not use statins as a comparator arm, or used a statin in both arms.
Risk of bias in 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.
Overall, the study quality was variable, with high risk of bias assessed in at least one domain for 5/7 studies (Almansob 2012; Mannacio 2008; Christenson 1999; Spadaccio 2010; Tamayo 2009). Only Prowle 2012 was considered truly to be at low risk of bias, with Chello 2006 assessed as unclear risk of bias based on identification of potential selection bias.
Allocation
Only three of the studies were assessed as low risk, with adequate description of randomisation methods including the use of computer generated algorithms (Almansob 2012; Mannacio 2008; Prowle 2012). The other four studies (Chello 2006; Christenson 1999; Spadaccio 2010; Tamayo 2009) made variable mention of randomisation, however they did not provide enough detailed information regarding actual randomisation procedures undertaken to determine risk of bias, and were therefore deemed to be unclear.
Blinding
Whilst the mention of 'blinding' was made in the majority of studies, the methods by which this was achieved were not clearly described. Only two of the studies made mention of use of placebo and the methods undertaken to administer this (Mannacio 2008; Prowle 2012). Despite this, the outcome measures of interest for this review (AKI, need for RRT, SCr, mortality and adverse events) are objective, and thus it was felt that whilst this represented poor reporting practices for the majority of the studies it did in fact constitute a low risk of bias for these outcome measures.
Incomplete outcome data
Most studies reported no loss to follow‐up or incomplete outcome data. This is likely secondary to the short follow‐up period, with no long‐term follow‐up undertaken in any study. Two studies reported patient drop out, with incomplete data collection. One study (Prowle 2012) reported a number of patient drop‐outs (15), however study results were not affected when reanalysed on a per protocol basis, with the primary analysis remaining as intention to treat. The missing data were evenly spread across groups (statin (8); control (7)) and dropout was for comparable reasons. Given this transparency, it was felt that this represented low risk of bias. The second study (Almansob 2012) reported that 19 patients were excluded from the analysis (statin (9), placebo (10)). The drop out was for comparable reasons, including liver dysfunction (statin (2), placebo (3)), and non‐completion not further defined (statin (4), placebo (6)). A further two patients in the statin group underwent surgery without cardiac bypass. Whilst these patients were excluded from the analysis, the dropout is even across groups and for comparable reasons, so again, was felt to represent low risk of bias.
Selective reporting
All the studies reported the outcomes that were prespecified in their methods. However, 5/7 studies were felt to have high risk of reporting bias (Almansob 2012; Christenson 1999; Mannacio 2008; Spadaccio 2010; Tamayo 2009) as drug studies would be expected to report adverse events as outcome data and these studies failed to do so. Prowle 2012 very clearly reported definitions of adverse events and event rate. Chello 2006 did report that no adverse drug related events were seen, however failed to define what constituted an event. As such, this was determined to be unclear risk of bias as judgement was unable to be made.
Other potential sources of bias
Christenson 1999 was industry funded, however made no mention of the role that this funding body played in the design and execution of the study or analysis of results, therefore risk of bias was deemed high. Two studies did not reporting funding and were deemed unclear (Mannacio 2008; Spadaccio 2010). No other potential sources of bias were identified.
Effects of interventions
See: Summary of findings for the main comparison
See summary of findings Table for the main comparison. Seven studies enrolling 662 participants were evaluated. Both fixed and random effects models were used in the initial analysis. No significant differences were found, therefore the summary estimates reported here were from the random effects models. Given the limited number of included studies, no sensitivity analysis was undertaken.
Postoperative AKI
Five studies (467 participants) reported postoperative AKI (Chello 2006; Prowle 2012; Christenson 1999; Spadaccio 2010; Mannacio 2008). There was no significant difference between groups in preventing postoperative AKI (Analysis 1.1 (5 studies, 467 participants): RR 0.76, 95% CI 0.46 to 1.28). There was no significant heterogeneity demonstrated (I2 = 0%). Despite the limited number of studies, a subgroup analysis by statin class was performed. For those studies using atorvastatin no statistically significant difference was seen in postoperative AKI between groups (Analysis 1.1.1 (3 studies, 190 participants): RR 0.83, 95% CI 0.46 to 1.49). For the single studies assessing simvastatin and rosuvastatin, no differences were seen between the groups (Analysis 1.1.2; Analysis 1.1.3). Subclass differences were assessed, with a calculated I2 of 34%, indicating a potential low level of variability amongst studies when considering result by statin subgroup. Whilst this may indicate different effects by statin (i.e. trends to benefit versus harm by class used), the low event rates overall and wide confidence intervals seen in conjunction with the low number of studies in each subgroup make it difficult to draw firm conclusions.
Postoperative serum creatinine
Three studies (195 participants) reported postoperative SCr (Almansob 2012; Prowle 2012; Tamayo 2009). Given differences in outcome reporting previously described, pooled analysis was only possible for two of these studies (Almansob 2012; Tamayo 2009 (195 participants). Statin treatment significantly decreased 24 hour postoperative SCr (Analysis 1.2 (2 studies, 195 participants): MD ‐21.25 µmol/L, 95% CI ‐31.09 to ‐11.41; I2 = 0%) with the result driven by differences seen in one study (Almansob 2012) which received 85.7% of the weighting. As data were available at two time points for this study, analysis of the 48 hour SCr was also significantly decreased in the statin group (Analysis 1.3 (2 studies, 195 participants): MD ‐20.97µmol/L, 95% CI ‐34.58 to ‐7.35; I2 = 12%). Given that Tamayo 2009) collected data to a maximum of 48 hours, the 72 hour time point was not undertaken.
Perioperative mortality
Mortality outcomes were reported in six studies (458 participants) (Almansob 2012; Chello 2006; Christenson 1999; Prowle 2012; Spadaccio 2010; Tamayo 2009). Given the universally short periods of follow‐up, low numbers of deaths were reported, all within the statin treatment arm of two studies (Almansob 2012; Tamayo 2009). Despite the individual studies showing trends to favour placebo for this outcome, there was no statistically significant difference in mortality seen between groups in the pooled analysis (Analysis 1.4 (6 studies, 458 participants): RR 3.86, 95% CI 0.43 to 34.40). There was no significant heterogeneity (I2 = 0%) seen. With low event rates demonstrated confidence intervals were extremely wide, again making any interpretation of these results difficult.
Need for postoperative renal replacement therapy
Need for postoperative RRT was reported in two studies (Almansob 2012; Prowle 2012). Almansob 2012 reported no need for RRT in either group and there were near equal numbers needing RRT reported in Prowle 2012. There was no statistically significant difference between statin treatment and placebo (Analysis 1.5 (2 studies, 251 participants): RR 0.80, 95% CI 0.23 to 2.81). There was no significant heterogeneity demonstrated (I2 = 0%)
Adverse events
Two studies (140 participants) reported adverse events however one study (Chello 2006) did not report adverse events related to statin use therefore no pooled analysis was undertaken. Prowle 2012 reported rise in ALT x 3 upper limit of normal, creatine kinase rise > 5000 IU/L and study drug cessation, the compared event rate between the groups did not reach statistical significance (P = 0.36, 0.36 and 1.0 respectively).
Prowle 2012 reported adverse events related to statin use. There was no significant difference in rise in ALT x 3 upper limit of normal (Analysis 1.6.1 (100 participants): RR 0.25, 95% CI 0.03 to 2.16), rise in creatine kinase > 5000 IU/L (Analysis 1.6.2 (100 participants): RR 4.00, 95% CI 0.46 to 34.54) or study drug cessation (Analysis 1.6.3 (100 participants): RR 1.33, 95% CI 0.31 to 5.65) between atorvastatin and placebo.
Discussion
Summary of main results
After a search of the literature, seven RCTs with a total of 662 participants that addressed the use of statin intervention prior to cardiac bypass surgery and its effects on perioperative kidney injury were identified. All the included studies assessed our prespecified primary outcome of AKI, or one of our secondary outcomes of SCr, need for RRT or adverse events, although with the exception of one (Prowle 2012), all kidney outcomes were considered as secondary within the original studies. Three studies assessed atorvastatin (Chello 2006; Prowle 2012; Spadaccio 2010; 190 participants), three studies assessed simvastatin (Almansob 2012; Christenson 1999; Tamayo 2009; 272 participants) and one study used rosuvastatin (Mannacio 2008; 200 participants), with high variability in drug washout period (24 hours (Prowle 2012) to more than one year (Chello 2006; Spadaccio 2010)). Duration of pre‐operative drug therapy ranged from treatment commencing on the operative day (Prowle 2012) to four weeks preoperatively (Christenson 1999). All studies were assessed as having a high risk of bias, with the exception of Prowle 2012 which was assessed as having a low risk of bias in all five assessed domains. Study follow‐up was uniformly short, with all the studies collecting data to hospital discharge, and biochemical data collection ranging from 24 hours postoperatively (Spadaccio 2010) up to seven days (Almansob 2012; Christenson 1999).
Overall for the outcome of AKI, the studies were variable in their results, however no individual study showed significant differences between statin treated and non‐drug treated groups. Our resultant meta‐analysis therefore showed no significant difference between the statin and comparator arms for incidence of AKI postoperatively (RR 0.76, 95% CI 0.46 to 1.28) (See summary of findings Table for the main comparison). The only finding of significance from all outcomes assessed was the difference in postoperative SCr between statin and placebo groups, an outcome which was measured in three studies (Almansob 2012; Prowle 2012; Tamayo 2009). Of these, significant variability in time‐point measurements allowed only two of the studies to be pooled for analysis. The third study (Prowle 2012) showed no significant difference in maximal SCr reached between postoperative days 1 to 5 between the statin and placebo arms (rise of 28 µmol/L (16 to 55) versus 29 (16 to 54), P = 0.62). In the meta‐analysis (Almansob 2012; Tamayo 2009), the group treated with statin showed a mean postoperative SCr of 21.25 µmol/L lower than the non‐drug treated group (95% CI ‐31.09 to ‐11.41, P < 0.0001). This result was largely driven through the strongly positive results in one study (Almansob 2012), where SCr data at 24, 48 and 72 hour time‐points showed a significant benefit of statin therapy over no drug treatment (24 hour (MD ‐23.30 µmol/L, 95% CI ‐33.93 to ‐12.67, P < 0.0001). For all other assessed outcomes (need for RRT, mortality, adverse events) no statistically or clinically significant difference was found between statin therapy and placebo or no therapy. Reliable conclusions were not able to be drawn from these analyses given the low numbers of studies reporting these outcomes, and concomitant low event rates.
Overall completeness and applicability of evidence
There are significant limitations to this review. Given the lack of large, high‐quality RCTs, our meta‐analysis was limited to small heterogeneous studies. Studies were conducted in a range of settings, from Europe to China and Australia, with potentially important socio‐demographic and procedural differences between the centres. Similarly, despite recruiting populations of adult patients undergoing cardiac bypass, the included studies had different protocols and preoperative treatment duration, with inclusions ranging from exclusively statin naive patients (Christenson 1999) to accepting different periods of drug washout, a setting unlikely to be seen in current clinical practice. For all studies but one (Prowle 2012), the statin was administered before the operative day, but the pre‐operative treatment duration ranged from seven days (Almansob 2012) to four weeks (Christenson 1999). In addition, different statins were used as part of these protocols. Three studies used atorvastatin (Chello 2006; Prowle 2012; Spadaccio 2010), three used simvastatin (Almansob 2012, Christenson 1999; Tamayo 2009) and Mannacio 2008 used rosuvastatin. To take into account this potential for different effects across drug formulation, subgroup analyses were performed. However given the small number of patients, the power to detect a difference is very limited. The outcomes of interest for this review were largely secondary outcomes within the included studies, and therefore lack of consensus definition for AKI was an issue. Two studies (Christenson 1999; Mannacio 2008) used SCr cut‐offs to dichotomise patients into AKI or no AKI (125 µmol/L for the first and 221µmol/L for the latter), while Prowle 2012 used the currently recommended RIFLE criteria (Bellomo 2004), which are based both on a ratio of peak over baseline SCr level and urinary outputs. Finally, two studies (Chello 2006; Spadaccio 2010) did not report their definition for AKI.
Overall, only minimal information about post‐operative kidney function was available in these reports as AKI was only a secondary outcome in all but one study (Prowle 2012). The event numbers were low for many outcomes, and therefore power to detect differences between the groups may be limited. The safety of statin use in surgery requiring cardiac bypass was unable to be assessed as a secondary outcome due to a lack of reported data in the majority of included studies.
Quality of the evidence
With the exception of Prowle 2012, all of the studies were assessed as having high risk of bias in at least one domain. Drug studies would be expected to report clearly on the presence or absence of adverse events related to drug administration, however only Prowle 2012 adequately assessed and reported these events. In addition, most studies stated that randomisation was undertaken, without describing the methods of randomisation, allocation concealment and blinding of study participants. In cases where blinding was stated to have occurred, several studies did not describe use of a placebo, raising significant questions as to how blinding could possibly have been adequate. Despite this, outcome measures in this case were objective and therefore most studies were assessed as low risk of bias in this domain. Authors of the included studies were therefore not contacted to further clarify randomisation strategies. Compliance to newly prescribed medication may well be poor, which would potentially significantly affect the outcomes of the included studies. None of the included studies measured or addressed the issue of compliance directly, although one (Christenson 1999) did measure serial lipid profiles to assess preoperative change in the setting of statin use. Overall, given that 6/7 included studies had identified high risk of bias in at least one domain in addition to significant differences in methodology and outcome reporting practices, the quality of the evidence was assessed as low or very low across all outcome measures (See summary of findings Table for the main comparison).
Potential biases in the review process
We believe that all relevant studies were identified. A thorough search strategy was devised and all major databases were searched for relevant studies, with no language restrictions applied. All three authors assessed the studies for inclusion in the review and the risk of bias, with discrepancy discussed between the three authors. The biggest limitation of the review process was that not all studies reported the outcome of interest or reported in a different fashion. This is related to the lack of thoroughly accepted definition for AKI. Despite attempting to obtain additional data, we were not able to obtain sufficient data to adequately classify all patients according to the RIFLE (Bellomo 2004) or AKIN (Mehta 2007) classification, and therefore our primary outcome (AKI) was considered as a dichotomous outcome rather than a stratified outcome based on reporting in the included studies. We did not include the results of unpublished studies. Studies with both positive and negative results were identified, making the possibility of publication bias less likely. No sensitivity analysis was able to be undertaken given the small number of studies eligible for inclusion in this review.
Agreements and disagreements with other studies or reviews
To our knowledge, this is the first completed review that assesses the impact of preoperative statin use for surgery requiring cardiac bypass on the incidence of postoperative AKI. However, there have been systematic reviews that examined multiple clinical outcomes with the use of preoperative statin therapy after cardiac surgery. A systematic review with meta‐analysis (Liakopoulos 2008) included more than 30,000 participants. It was shown that statin therapy had no effect on postoperative kidney failure (OR 0.78, 95% CI 0.46 to 1.31). This was in agreement with our findings. However, it reported an incidence of 4.1% kidney failure in a total of 6408 patients. This was much lower than our incidence of 10.3% AKI out of total of 467 patients. The discrepancy could be due to the fact that the majority of studies included in Liakopoulos 2008 were retrospective observational studies (only two small RCTs out of five studies), whereas this review included five RCTs for this particular analysis. There was also significant heterogeneity observed in Liakopoulos 2008 (P = 0.05; I2 = 58.3%).
In a more recent Cochrane review performed by the same author (Liakopoulos 2012), four studies reported the incidence of kidney failure in a total of 367 participants. The incidence of kidney failure was 3.2% in the statin group compared to 7.1% in the control group. This Cochrane analysis showed that statin treatment did not lead to a significant reduction of the odds of kidney failure (OR 0.41, 95% CI 0.15 to 1.12; P = 0,08). Our analysis also did not show any statistically significant difference between the two groups (RR 0.76; 95% CI: 0.46 to 1.28). A significant difference between our analysis and the previous Cochrane review related to inclusion in this review of a recent RCT reporting the outcome of AKI (Prowle 2012). It was a well‐designed study with low risk of bias and it carried an important weight in the pooled analysis. In Prowle 2012, there were 13/50 patients with AKI in the statin group compared to 16/50 in the placebo group, (RR 0.81, 95% CI 0.44 to 1.51). This result would have likely attenuated the statistical trend observed in Liakopoulos 2008.
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.
Comparison 1 Statins versus placebo/no treatment, Outcome 1 Acute kidney injury.
Comparison 1 Statins versus placebo/no treatment, Outcome 2 Serum creatinine: 24 h postoperatively.
Comparison 1 Statins versus placebo/no treatment, Outcome 3 Serum creatinine: 48 h postoperatively.
Comparison 1 Statins versus placebo/no treatment, Outcome 4 Mortality.
Comparison 1 Statins versus placebo/no treatment, Outcome 5 Renal replacement therapy.
Comparison 1 Statins versus placebo/no treatment, Outcome 6 Adverse events.
| Statin therapy compared with placebo for reduction in AKI after cardiac surgery with bypass | ||||||
| Patient or population: adults undergoing surgery requiring cardiac bypass Settings: hospital inpatients Intervention: statin treatment prior to cardiac bypass surgery Comparison: placebo or no drug therapy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No. of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo or no drug therapy | Statins | |||||
| Acute kidney injury Follow‐up: ICU stay | 27/232 (11.6%) | 21/235 (8.9%) | RR 0.76 (0.46 to 1.28) | 467 (5) | ⊕⊕⊝⊝ | No significant difference. High risk of bias in most studies |
| Serum creatinine Follow‐up: first 72 h post‐operative | The mean serum creatinine ranged across control groups from 77.6 to 106 µmol/L | The mean serum creatinine in intervention groups was on average 21 µmol/L lower (95% CI ‐31.09 to ‐11.41) | 195 (2) | ⊕⊕⊝⊝ | Significant difference, both studies have high risk of bias | |
| Renal replacement therapy Follow‐up: ICU stay | 5/124 (4.0%) | 4/127 (3.1%) | RR 0.8 (0.23 to 2.81) | 251 (2) | ⊕⊝⊝⊝ | No significant difference. Only one study reported the need for renal replacement therapy |
| Mortality Follow‐up: hospital stay | 0/189 (0%) | 3/192 (1.6%) | RR 3.86 (0.43 to 34.4) | 381 (5) | ⊕⊝⊝⊝ | No significant difference. Very low event rate. High risk of bias amongst studies |
| Adverse events Follow‐up: treatment duration | 8/70 (11.4%) | 9/70 (12.9%) | RR 1.13 (1.47 to 2.68) | 140 (1) | ⊕⊝⊝⊝ | No significant difference. Only one study adequately reported adverse events |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| ICU ‐ intensive care unit | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Acute kidney injury Show forest plot | 5 | 467 | Risk Ratio (M‐H, Random, 95% CI) | 0.76 [0.46, 1.28] |
| 1.1 Atorvastatin | 3 | 190 | Risk Ratio (M‐H, Random, 95% CI) | 0.83 [0.46, 1.49] |
| 1.2 Simvastatin | 1 | 77 | Risk Ratio (M‐H, Random, 95% CI) | 0.35 [0.10, 1.21] |
| 1.3 Rosuvastatin | 1 | 200 | Risk Ratio (M‐H, Random, 95% CI) | 3.0 [0.32, 28.35] |
| 2 Serum creatinine: 24 h postoperatively Show forest plot | 2 | 195 | Mean Difference (IV, Random, 95% CI) | ‐21.25 [‐31.09, ‐11.41] |
| 2.1 Simvastatin | 2 | 195 | Mean Difference (IV, Random, 95% CI) | ‐21.25 [‐31.09, ‐11.41] |
| 3 Serum creatinine: 48 h postoperatively Show forest plot | 2 | 195 | Mean Difference (IV, Random, 95% CI) | ‐20.97 [‐34.58, ‐7.35] |
| 3.1 Simvastatin | 2 | 195 | Mean Difference (IV, Random, 95% CI) | ‐20.97 [‐34.58, ‐7.35] |
| 4 Mortality Show forest plot | 6 | 458 | Risk Ratio (M‐H, Random, 95% CI) | 3.86 [0.43, 34.40] |
| 4.1 Atorvastatin | 3 | 190 | Risk Ratio (M‐H, Random, 95% CI) | 5.00 [0.25, 101.58] |
| 4.2 Simvastatin | 3 | 268 | Risk Ratio (M‐H, Random, 95% CI) | 2.88 [0.12, 69.70] |
| 5 Renal replacement therapy Show forest plot | 2 | 251 | Risk Ratio (M‐H, Random, 95% CI) | 0.8 [0.23, 2.81] |
| 5.1 Atorvastatin | 1 | 100 | Risk Ratio (M‐H, Random, 95% CI) | 0.8 [0.23, 2.81] |
| 5.2 Simvastatin | 1 | 151 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 6 Adverse events Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 6.1 ALT x 3 ULN | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Creatinine kinase > 5000 IU/L | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Study drug cessation | 1 | Risk Ratio (M‐H, Random, 95% CI) | 0.0 [0.0, 0.0] | |
