preoperative statin therapy for patients undergoing ...statins (hmg-coa reductase inhibitors) have...

Preoperative statin therapy for patients undergoing cardiac

surgery (Review)

Liakopoulos OJ, Kuhn EW, Slottosch I, Wassmer G, Wahlers T

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 4

http://www.thecochranelibrary.com

Preoperative statin therapy for patients undergoing cardiac surgery (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .

6BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

16DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

18ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

19REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

25CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Outcomes, Outcome 1 Mortality. . . . . . . . . . . . . . . . . . . . 48

Analysis 1.2. Comparison 1 Outcomes, Outcome 2 Myocardial infarction. . . . . . . . . . . . . . . . 48

Analysis 1.3. Comparison 1 Outcomes, Outcome 3 Atrial fibrillation. . . . . . . . . . . . . . . . . . 49

Analysis 1.4. Comparison 1 Outcomes, Outcome 4 Stroke. . . . . . . . . . . . . . . . . . . . . 50

Analysis 1.5. Comparison 1 Outcomes, Outcome 5 Renal failure. . . . . . . . . . . . . . . . . . . 50

Analysis 1.6. Comparison 1 Outcomes, Outcome 6 Length of stay on ICU. . . . . . . . . . . . . . . 51

Analysis 1.7. Comparison 1 Outcomes, Outcome 7 Length of stay in hospital. . . . . . . . . . . . . . . 52

Analysis 2.1. Comparison 2 Only studies with CABG procedures, Outcome 1 Myocardial infarction. . . . . . . 53

Analysis 2.2. Comparison 2 Only studies with CABG procedures, Outcome 2 Atrial fibrillation. . . . . . . . 54

Analysis 2.3. Comparison 2 Only studies with CABG procedures, Outcome 3 Stroke. . . . . . . . . . . . 55

Analysis 2.4. Comparison 2 Only studies with CABG procedures, Outcome 4 Renal failure. . . . . . . . . . 55

Analysis 2.5. Comparison 2 Only studies with CABG procedures, Outcome 5 Length of stay on ICU. . . . . . 56

Analysis 2.6. Comparison 2 Only studies with CABG procedures, Outcome 6 Length of stay in hospital. . . . . 57

Analysis 3.1. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 1 Myocardial infarction. . 58

Analysis 3.2. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 2 Atrial fibrillation. . . . 59

Analysis 3.3. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 3 Stroke. . . . . . . . 59

Analysis 3.4. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 4 Renal failure. . . . . 60

Analysis 3.5. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 5 Length of stay on ICU. . 61

Analysis 3.6. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 6 Length of stay in hospital. 62

Analysis 4.1. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 1 Myocardial infarction. . 63

Analysis 4.2. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 2 Atrial fibrillation. . . . 64

Analysis 4.3. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 3 Stroke. . . . . . . . 65

Analysis 4.4. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 4 Renal failure. . . . . 65

Analysis 4.5. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 5 Length of stay on ICU. . 66

Analysis 4.6. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 6 Length of stay in hospital. 67

Analysis 5.1. Comparison 5 Only studies with ATORVASTATIN, Outcome 1 Myocardial infarction. . . . . . . 68

Analysis 5.2. Comparison 5 Only studies with ATORVASTATIN, Outcome 2 Atrial fibrillation. . . . . . . . 68

Analysis 5.3. Comparison 5 Only studies with ATORVASTATIN, Outcome 3 Stroke. . . . . . . . . . . . 69

Analysis 5.4. Comparison 5 Only studies with ATORVASTATIN, Outcome 4 Renal failure. . . . . . . . . . 69

Analysis 5.5. Comparison 5 Only studies with ATORVASTATIN, Outcome 5 Length of stay on ICU. . . . . . 70

Analysis 5.6. Comparison 5 Only studies with ATORVASTATIN, Outcome 6 Length of stay in hospital. . . . . 71

Analysis 6.1. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 1 Myocardial infarction. 71

Analysis 6.2. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 2 Atrial fibrillation. . 72

Analysis 6.3. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 3 Renal failure. . . 73

iPreoperative statin therapy for patients undergoing cardiac surgery (Review)


Analysis 6.4. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 4 Length of stay on ICU. 74

Analysis 6.5. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 5 Length of stay in

hospital. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

75APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

78CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

79SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiPreoperative statin therapy for patients undergoing cardiac surgery (Review)


[Intervention Review]

Preoperative statin therapy for patients undergoing cardiacsurgery

Oliver J Liakopoulos1 , Elmar W Kuhn1, Ingo Slottosch1, Gernot Wassmer2, Thorsten Wahlers1

1Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany. 2Department for Medical Statistics,

Informatics and Epidemiology, University of Cologne, Cologne, Germany

Contact address: Oliver J Liakopoulos, Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Kerpener Strasse

62, Cologne, 50924, Germany. [email protected].

Editorial group: Cochrane Heart Group.

Publication status and date: New, published in Issue 4, 2012.

Review content assessed as up-to-date: 28 September 2010.

Citation: Liakopoulos OJ, Kuhn EW, Slottosch I, Wassmer G, Wahlers T. Preoperative statin therapy for patients undergoing cardiac

surgery. Cochrane Database of Systematic Reviews 2012, Issue 4. Art. No.: CD008493. DOI: 10.1002/14651858.CD008493.pub2.


A B S T R A C T

Background

Patients referred to cardiac surgery for cardiovascular disease are at significant risk for the development of post-operative major adverse

events despite significant advances in surgical techniques and perioperative care. Statins (HMG-CoA reductase inhibitors) have gained

a pivotal role in the primary and secondary prevention of coronary artery disease, and are thought to improve perioperative outcomes

in patients undergoing cardiac surgery.

Objectives

To determine the effectiveness of a preoperative statin therapy in patients undergoing cardiac surgery.

Search methods

We searched CENTRAL (Issue 2 of 4, 2010 on The Cochrane Library), MEDLINE (1950 to May, Week 1 2010), EMBASE (1980 to

2010 Week 19), and the metaRegister of Controlled Trials. Additionally, ongoing trials were searched through the National Research

Register, the ClinicalTrials.gov registry and grey literature. Conference indices from relevant scientific meetings (2006-2009) were

screened online for eligible trials. No language restrictions were applied.

Selection criteria

All randomized controlled trials comparing any statin treatment before cardiac surgery, for any given duration and dose, to no

preoperative statin therapy (standard of care) or placebo.

Data collection and analysis

Two authors evaluated trial quality and extracted data from titles and abstracts identified from the electronic database searches according

to pre-defined criteria. Accordingly, full text articles of potentially relevant studies that met the inclusion criteria were retrieved to assess

definite eligibility for inclusion. Effect measures are reported as odds ratios (OR) or weighted mean difference (WMD) with 95%

confidence intervals (95%-CI).

1Preoperative statin therapy for patients undergoing cardiac surgery (Review)


mailto:[email protected]

Main results

Eleven randomized controlled studies including a total of 984 participants undergoing on- or off-pump cardiac surgical procedures were

identified. Pooled analysis showed that statin pre-treatment before surgery reduced the incidence of post-operative atrial fibrillation

(AF) (OR 0.40; 95%-CI: 0.29 to 0.55; p<0.01), but failed to influence short-term mortality (OR 0.98, 95%-CI: 0.14 to 7.10; p=0.98)

or post-operative stroke (OR 0.70, 95%-CI: 0.14 to 3.63; p=0.67). In addition, statin therapy was associated with a shorter length of

stay of patients on the intensive care unit (ICU) (WMD: -3.39 hours; 95%-CI: -5.77 to -1.01) and in-hospital (WMD: -0.48 days;

95%-CI: -0.85 to -0.11) where significant heterogeneity was observed. There was no reduction in myocardial infarction (OR 0.52;

95%-CI: 0.2. to 1.30) or renal failure (OR 0.41; 95%-CI: 0.15 to 1.12). These results were unaffected after subgroup analysis. No

major or minor perioperative statin side-effects were reported from trials investigating this safety endpoint.

Authors’ conclusions

Preoperative statin therapy reduces the odds of post-operative AF and shortens the stay on the ICU and in the hospital. Statin

pretreatment had no influence on perioperative mortality, stroke, myocardial infarction or renal failure. Since analysed studies included

mainly patients undergoing myocardial revascularizations the results cannot be extrapolated to patients undergoing other cardiac

procedures such as heart valve or aortic surgery.

P L A I N L A N G U A G E S U M M A R Y

Preoperative statin therapy for patients undergoing cardiac surgery

Cardiac surgery offers a highly efficient therapeutic option to patients with heart disease, but bears at the same time a significant risk of

the development of post-operative adverse events. Despite the increasing proportion of patients referring to cardiac surgery with major

comorbidities, the operative results have remained stable during the past decades due to significant advancements of surgical techniques.

Nonetheless, perioperative care of patients referring to cardiac surgery still needs to be optimized to further improve patients´ outcomes.

Statins (HMG-CoA reductase inhibitors) are known to provide beneficial effects beyond their lipid-lowering properties in patients with

atherosclerotic cardiovascular disease in terms of a reduction of mortality from adverse cardiovascular events. However, evidence for

the beneficial statin effects for patients undergoing cardiac surgery is inconsistent since it is mainly extracted from observational studies

and only a few small randomized clinical trials.

The aim of this review is to determine the current evidence of preoperative statin therapy on the reduction of major adverse cardiovascular

events in patients referred to cardiac surgical procedures.

We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and the metaRegister of Controlled Trials.

Eleven studies dating from 1999 to 2010 with a total of 984 participants undergoing cardiac surgical procedures were identified. All

included trials were randomized studies comparing statin treatment with a control intervention (no statin medication) or placebo in

patients that were predominantly referred to coronary artery bypass grafting surgery.

Preoperative statin therapy resulted in a reduction of post-operative AF and a shorter length of stay both on the ICU and in the hospital.

Although statin-pretreatment was associated with lower incidences of myocardial infarction and renal failure, these results did not reach

statistical significance. Furthermore, statin therapy had no impact on short-term mortality and post-operative stroke. No serious side

effects of a statin therapy prior to cardiac surgery were reported. However, all analysed studies included mainly patients undergoing

coronary bypass operations, thus, the results of this study may not be generalisable to patients undergoing cardiac procedures other

than coronary artery bypass grafting.



S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Statin therapy for patients undergoing cardiac surgery

Patient or population: patients with patients undergoing cardiac surgery

Settings: cardiac surgery

Intervention: statin pretreatment versus control

Outcomes Illustrative comparative risks* (95% CI) Relative effect

(95% CI)

No of Participants

(studies)

Quality of the evidence

(GRADE)

Comments

Assumed risk Corresponding risk

Control Statin therapy

Mortality

Follow-up: mean 16.4

days

Study population OR 0.98

(0.14 to 7.1)

200

(1 study)

⊕⊕⊕⊕

high

6 per 1000 6 per 1000

(1 to 41)

Medium risk population

0 per 1000 0 per 1000

(0 to 0)

Myocardial infarction

ECG/cardiac enzymes


days


(0.2 to 1.3)

897

(9 studies)

⊕⊕⊕⊕

high

27 per 1000 14 per 1000

(6 to 35)


15 per 1000 8 per 1000

(3 to 19)

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Atrial fibrillation

ECG


days


(0.29 to 0.55)

841

(8 studies)

⊕⊕⊕⊕

high

356 per 1000 181 per 1000

(138 to 233)

Low risk population

200 per 1000 91 per 1000

(68 to 121)

High risk population

400 per 1000 211 per 1000

(162 to 268)

Stroke


days

16 per 1000 11 per 1000

(2 to 56)

OR 0.7

(0.14 to 3.63)

374

(5 studies)

⊕⊕⊕⊕

high

Renal failure

serum creatinin/urea


days


(0.15 to 1.12)

367

(4 studies)

⊕⊕⊕⊕

high

71 per 1000 30 per 1000

(11 to 79)


45 per 1000 19 per 1000

(7 to 50)

Length of stay on ICU


hours

The mean Length of stay

on ICU in the intervention

groups was

3.39 hours lower

(5.77 to 1.01 lower)

521

(7 studies)

⊕⊕⊕⊕

high

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Length of stay in hospi-

tal


days

The mean Length of stay

in hospital in the interven-

tion groups was

0.48 days lower

(0.85 to 0.11 lower)

877

(8 studies)

⊕⊕⊕⊕

high

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the

assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; OR: Odds ratio;

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.

Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low quality: We are very uncertain about the estimate.

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B A C K G R O U N D

Patients undergoing on- or off-pump cardiac surgery are still at

significant risk for post-operative major adverse cardiovascular

events (Alexander 2008; Gummert 2009; Serruys 2009; Verrier

2004). During the past decade, overall mortality within 30 days

of surgery has remained constant worldwide at ~3-4% (Gummert

2009; Serruys 2009). In contrast, the presence of increasing co-

morbidities in the constantly ageing patient population has led to a

substantial post-operative increase in the rate of major adverse car-

diac events ranging from 5% in low-risk (Gummert 2009; Serruys

2009) to 15% in moderate- to high-risk cohorts (Alexander 2008;

Verrier 2004). If outcomes among cardiac surgery patients are

to be improved, development of better strategies that limit the

risk of major adverse events after cardiac procedures is impera-

tive. HMG-CoA reductase inhibitors (statins) effectively reduce

the risk of atherosclerotic cardiovascular disease through lipid-

lowering actions. They have gained a pivotal role in the primary

and secondary prevention of cardiovascular events (Brugts 2009;

Sacks 1996), including patients after coronary artery bypass graft-

ing (CABG) (Knatterud 2000; White 2001). For patients with

coronary artery disease (CAD), current guidelines of the ACC/

AHA and NCEP recommend a statin therapy when serum LDL-

levels are higher than 100 mg/dl (Grundy 2004). Nonetheless,

only ~50% of cardiac surgery patients admitted for CABG receive

statins and even fewer patients achieve sufficient lipid-levels prior

to coronary surgery in compliance with existing guidelines (Kulik

2007). In addition, beyond their lipid-lowering actions, statins

have been suggested to exert lipid-independent pleiotropic effects

that may offer additional cardiovascular protection (Di 2009; Patti

2005; Patti 2007). Consequently, the present systematic review

aims to assess the strength of evidence from RCTs for the use of

preoperative statin therapy in terms of a reduction in early all-

cause mortality and decreases in incidence of major adverse post-

operative events post cardiac surgery.

Description of the condition

Healthcare costs related to CAD add up to more than six billion

Euros per year in Germany alone. A total of 700,000 percuta-

neous coronary interventions (PCI) and 100,000 cardiac surgery

procedures are performed annually, with coronary artery revascu-

larisation surgery (i.e. CABG) accounting for approximately 50-

60% of cardiac procedures (Gummert 2009). Despite major ad-

vances in myocardial preservation, pharmacological interventions

and the introduction of minimal invasive techniques (off-pump

surgery), patients undergoing cardiac surgery are still at substan-

tial risk for early post-operative adverse cardiovascular compli-

cations such as myocardial infarction (MI), cardiac arrhythmias,

stroke and renal failure (Mohammed 2009; Serruys 2009; Verrier

2004). When considering the high numbers of cardiac surgeries

performed worldwide, further reduction of perioperative morbid-

ity and mortality will significantly impact the economic burden

on public healthcare costs.

Accumulating evidence from RCTs has demonstrated the efficacy

of pre-operative statin therapy in reducing periprocedural cardio-

vascular events after PCI and non-cardiac surgery when compared

to statin naive patients (Di 2009; Lindenauer 2004; Patti 2005;

Patti 2007; Poldermans 2003; Schouten 2009), thereby making

a pre-operative treatment with statins a promising approach to

reduce post-operative morbidity and mortality in patients sched-

uled for cardiac surgery. However, in patients undergoing car-

diac surgery, results are conflicting, with several studies report-

ing a decrease in short-term mortality and major cardiovascular

events including MI, atrial fibrillation (AF), stroke, and renal fail-

ure in patients receiving preoperative statins (Clark 2006; Col-

lard 2006; Mannacio 2008; Pan 2004; Patti 2006), while others

have failed to show a beneficial effect of statins on these endpoints

(Ali 2005; Christenson 1999; Coleman 2007; Powell 2007; Thiel-

mann 2007). Previous systematic reviews performed by our group

and others that aimed to assess the potential clinical benefits of

pre-operative statin therapy in cardiac surgery included predomi-

nantly non-RCTs. The reviewers also highlighted the lack of sig-

nificant heterogeneity and the risk of publication bias, making in-

terpretation of the reported results difficult (Chen 2010; Hindler

2006; Kapoor 2006; Liakopoulos 2008; Takagi 2009, Yin 2010).

For example, in the largest comprehensive meta-analysis in cardiac

surgery consisting of 31,725 patients undergoing predominately

CABG (92%), statin pre-treatment was associated with a substan-

tial post-operative reduction in the odds of early mortality (OR

0.57; 95%CI: 0.49-0.6; p<0.001), stroke (OR 0.74, 95%CI: 0.60-

0.91; p=0.004) and AF (OR 0.67, 95%CI: 0.51-0.88; p=0.004)

when compared to non-treated patients (Liakopoulos 2008). De-

spite these promising observations from predominantly observa-

tional trials in favor of a statin therapy prior to cardiac surgery,

final evidence from RCTs supporting the use of statins before car-

diac surgery for prevention of major adverse post-operative events

is still inconclusive. This is largely due to the absence of large-scale

RCTs, and existing RCTs being inadequately powered to detect

significant differences in relevant short-term clinical outcomes.

Description of the intervention

The current systematic review is aimed at analysing data from

RCTs that evaluate the impact of pre-operative statin intake on the

reduction of major adverse events in patients undergoing cardiac

surgery.

How the intervention might work

Cardiac surgery related trauma, cardioplegic cardiac arrest, the use

of cardiopulmonary bypass (CPB) with unphysiological organ per-

fusion cause two complex interrelated pathophysiological states



termed ischemia/reperfusion injury and systemic inflammatory

response (SIRS) (Paparella 2002). Proposed mechanisms mediat-

ing organ damage include activation of leukocytes and endothelial

cells, as well as alterations in oxidative stress, calcium homeosta-

sis, and generation of inflammatory cytokines. Numerous stud-

ies have demonstrated an association between the systemic release

of pro-inflammatory cytokines and post-operative adverse clini-

cal outcomes including mortality (Bourbon 2004; Deng 1996;

Hennein 1994). Beyond systemic inflammation, various reports

suggest that local induction of inflammatory cytokines in the heart

(Liakopoulos 2005; Liakopoulos 2006a; Liakopoulos 2007; Valen

2001; Valen 2000), lungs, and remote organs (Liakopoulos 2007;

Muhlfeld 2008; Qing 2001) may substantially contribute to post-

operative organ dysfunction after cardiac surgery.

In addition to their lipid-lowering actions, statins are thought to

exert multiple “pleiotropic” effects, including improvement of en-

dothelial function, plaque stabilization, decrease of inflammatory

markers and attenuation of myocardial ischemia-reperfusion in-

jury (Chello 2006; Lazar 2003; Liakopoulos 2006; Ludman 2009).

Statins have been demonstrated to increase endothelial NO-pro-

duction through the PI3K-Akt-eNOS pathway, inhibit expression

of pro-inflammatory mediators and decrease myocardial injury

after cardiac surgery (Brull 2001; Chello 2007; Lazar 2003; Li-

akopoulos 2006; Ludman 2009; Mannacio 2008). These obser-

vations from experimental and preliminary clinical studies under-

score potentially relevant mechanisms through which statins may

substantially contribute to direct organ protection and contribute

to the improvement of post-operative outcomes in patients under-

going cardiac surgery (Patti 2007; Mannacio 2008). In fact, recent

evidence from clinical studies have demonstrated that the bene-

ficial pleiotropic statin effects may wane over time after chronic

statin treatment (>two weeks) and can be recaptured by an acute

high preprocedural statin reloading dose (Di 2009).

Why it is important to do this review

In view of the absence of large RCTs and the limited clarity of

data from existing small RCTs and observational trials, further ev-

idence is needed in order to evaluate whether a pre-operative statin

therapy may improve post-operative outcomes in patients under-

going cardiac surgery. Existing evidence from previous systematic

reviews underline the potential benefits of statin-intake prior to

cardiac surgery (Liakopoulos 2008; Takagi 2009), but conclusions

are predominantly drawn from observational trials. However, dur-

ing the past two years several smaller RCTs have been added to

the literature, for the first time allowing a robust analysis of the

strength of evidence for a pre-operative statin treatment on the

reduction of post-operative adverse outcomes after cardiac surgery

based exclusively on data from RCTs. In addition, this system-

atic review will be updated in a continuous fashion (every two

years) and all currently conducted or planned RCTs will be added

over time to accumulate the best evidence for this topic. Further-

more, when considering that only ~50% of cardiac surgery patients

scheduled for CABG surgery receive statins in compliance with

existing guidelines of the ACC/AHA and NCEP (Grundy 2004;

Kulik 2007), the proposed systematic review provides conclusive

data that will enable valid recommendations towards optimizing

the peri-operative care of cardiac surgery patients.

O B J E C T I V E S

To determine the effectiveness of pre-operative statin therapy in

patients undergoing cardiac surgery.

M E T H O D S

Criteria for considering studies for this review

Types of studies

All RCTs irrespective of sample size, publication status or language

that allow short (hospitalization period) or mid-term (30 days post

surgery) assessment of relevant post-operative clinical endpoints.

Types of participants

All adult patients (age>18 years) undergoing on- or off-pump car-

diac surgery procedures (i.e. CABG, valve surgery or combined

procedures including aortic surgery) were included, regardless of

redo or emergency operations. Patients were included regardless of

their pre-operative left ventricular ejection fraction, renal function

and pre-operative heart rhythm status (i.e. AF). Patients undergo-

ing heart transplantation or corrective surgery for congenital heart

defects were excluded to minimise potential confounders (i.e. im-

munosuppressive therapy, complexity of underlying disease and

surgery, age).

Types of interventions

All RCTs were selected that compared any statin treatment before

cardiac surgery for any given duration and dose to:

-no pre-operative statin therapy (standard care) or

-placebo.

Co-interventions were allowed as long as all arms of the ran-

domised allocation received the same co-intervention. Adherence

to the perioperative statin treatment was clarified by analysing the

RCT reports and contacting the authors if additional information

was needed. Any inconsistencies are reported.



Types of outcome measures

Primary and secondary outcomes are defined a priori as follows:

Primary outcomes

Short-term post-operative mortality (i.e. in-hospital or 30-day

mortality)

Secondary outcomes

1) MI

2) AF - any type

3) Stroke

4) Renal failure

5) Length of stay on the Intensive Care Unit (ICU) and hospital

6) adverse effects related to statin therapy

Since uniform definition for MI among clinical trials poses a sig-

nificant problem, the authors accepted the definition of MI ap-

plied by the included RCTs. Similarly to MI, post-operative renal

failure was recorded following the authors definitions: AF was de-

fined as occurrence of any type or new-onset post-operative AF;

stroke was commonly defined in the presence of clinical or radio-

logical evidence for neurological deficit or defect.

Search methods for identification of studies

Electronic searches

The Cochrane Central Register of Controlled Trials (CENTRAL,

Issue 2 of 4, 2010 on The Cochrane Library), Ovid MEDLINE

(1950 to May Week 1 2010) and Ovid EMBASE (1980 to 2010

Week 19) have been searched on 17 May 2010 (see Appendix

1 for the search strategies). The Cochrane sensitive-maximizing

search strategy for identifying randomized trials has been applied

to MEDLINE and EMBASE (Lefebvre 2009). No language re-

strictions were applied.

Searching other resources

We searched the metaRegister of Controlled Tri-

als (mRCT, www.controlled-trials.com/mrct), ClinicalTrials.gov (

www.clinicaltrials.gov) and the National Research Register (http://

www.controlled-trials.com/mrct/archived) for ongoing or past tri-

als. For grey literature we searched OpenGrey (System for Infor-

mation on Grey Literature in Europe, http://www.opengrey.eu/).

Conference indices from the past three years scientific meetings

(2006-2009) of the Society of Thoracic Surgeons (STS), European

Association of Cardiothoracic Surgery (EACTS), American Asso-

ciation of Thoracic Surgery (AATS), European Society of Cardiol-

ogy (ESC), American College of Cardiology (ACC) and American

Heart Association (AHA) were screened online for eligible trials.

Authors and experts in this field were contacted to ask if there were

any known ongoing research either being conducted or completed

but unpublished. Reference lists of eligible trials and reviews were

be checked for further relevant studies.

Data collection and analysis

Selection of studies

Two authors (OJL and EWK) performed the literature searches

using the above mentioned prespecified search strategy. All titles

and abstracts from the electronic search were uploaded into a ref-

erence management software database. Both reviewers indepen-

dently assessed trials from titles and abstract identified from the

electronic database searches according to the pre-defined criteria.

If both reviewers declared a citation for not relevant, it was ex-

cluded. Disagreements were solved by consensus and after discus-

sion with a third reviewer (Ingo Slottosch).

In a second step, full-text articles of potentially relevant studies

that meet the pre-defined inclusion criteria were retrieved to as-

sess definite eligibility for inclusion. If both reviewers excluded

a study concordantly, reasons for exclusion were noted. Further

disagreement were solved by discussion with the third reviewer if

no consensus was reached. Numbers of references retrieved from

the search strategy, excluded and included studies were recorded

according to the QUOROM (i.e. now PRISMA) statement and

are presented in a flow chart (Moher 1999; Moher 2009).

Data extraction and management

The following data were extracted by two authors (OJL and EWK)

and entered in standard data collection table:

All data in regards to authorship, article title, year of publication,

type of publication (abstract, oral presentation, full-text study),

study design, study population (sample size, age, sex, medications,

comorbidities, type of cardiac operation), length of preoperative

statin exposure, applied statin regimen (statin type and dose),

length of follow-up and the above mentioned clinical endpoints

were extracted.

If needed, missing data, information or clarification about the pre-

sented results were retrieved by directly contacting the correspond-

ing author of the study.

Assessment of risk of bias in included studies

Methodological quality of included studies were assessed by two

independent authors (OJL and EWK) for adequacy of sequence

generation, allocation concealment, blinding (participants, per-

sonnel and outcome), drop-out rates (incomplete outcome data),

analysis of intention-to-treat (ITT), selective outcome reporting

and other bias using the established standards of the Cochrane

Collaboration (Cochrane Handbook Version. 5.0.2, table 8.5a-

c). Studies were labelled according to recommendation of the



http://www.controlled-trials.com/mrct



http://www.clinicaltrials.gov

http://www.controlled-trials.com/mrct/archived






http://www.opengrey.eu/



Cochrane Handbook (table 8.7a: “Yes”, low risk of bias; “No”,

high risk of bias; “Unclear”, unclear risk of bias) [Higgins 2008]

and are presented in a “risk of bias summary” figure as depicted

in the Cochrane Handbook by cross-tabulation of studies (Figure

8.6c).

Missing information mandatory for the assessment of risk for bias

of the report were resolved by directly contacting the correspond-

ing author.

Measures of treatment effect

Statistical analyses was performed using the latest version of the

Review Manager (Version 5.1.1). All dichotomous outcome data

were analysed and presented in form of odds ratios (OR) and 95%

confidence intervals (95% CI) so that an OR < 1 favours statin

treatment over control. For continuous scales (i.e. length of stay on

ICU and hospital), the weighted mean difference (WMD) was cal-

culated. In studies reporting the median and the quartiles, authors

were contacted to retrieve the mean values with standard devia-

tions. If not feasible, the median was assumed to most accurately

represent the tendency and treated as the mean. Data are presented

in forest plots and weighted pooled effects calculated using either

a standard fixed-effect model (Mantel-Haenszel method) or a ran-

dom-effects model (DerSimonian-Laird method) in the absence

or presence of heterogeneity, respectively, and as defined below.

Unit of analysis issues

Cross-over or cluster-randomised trial were not found and in-

cluded into this review. Care was taken to identify trials with mul-

tiple treatment groups and clearly distinguish between statin and

no-statin therapy.

Dealing with missing data

If necessary, all missing data, information or clarification about

the presented data set was retrieved by contacting the primary

authors of the study. In case of missing data due to loss to follow-

up, a worst case scenario analysis was performed regarding the

primary outcome. This analysis assumed that participants in the

treatment group that were lost to follow-up had the worst outcome

while patients in the control group that lost to follow-up had the

best outcome. Results of this worst case scenario analysis were

compared with the primary analysis investigating any parallel or

different trends.

Assessment of heterogeneity

Q- and I²-statistics were performed to test for heterogeneity be-

tween included studies. A standard fixed-effect model (Mantel-

Haenszel method) was used in the absence of heterogeneity among

studies (chi-square p>0.1 and I²<50%). In the presence of sub-

stantial heterogeneity the DerSimonian and Laird random-effects

model was applied (chi-square P<0.1 or I²>50%) (Higgins 2002).

If present, heterogeneity was investigated by subgroup analysis as

mentioned below. Meta-regression was performed in case of ad-

equate number of studies (>10 studies per analysed outcome) to

investigate the impact of relevant covariates of studies on the statin

effect estimates.

Assessment of reporting biases

A funnel plot (depicted as effects estimate against standard er-

ror) was constructed to visually inspect and assess the presence of

publication bias and to examine differences between the outcome

effects of large and small studies. Additionally, publication bias

was analysed by applying the Egger´ s weighted regression statistic

(Egger 1997) to test for funnel plot asymmetry. Correction for

publication bias was performed using the Trim-and-Fill method

described by Duval and Tweedie (Duval 2000) that approximates

the number of unpublished studies needed to achieve symmetry of

the funnel plot, thereby recalculating an adjusted effect estimate

(MIX software package, Version 1.61) (Bax 2006). Multiple pub-

lication and language bias were addressed by excluding redundant

reports of authors analysing the same patient cohort and by not

applying any language restrictions during the search strategy.

Data synthesis

In general, a meta-analysis was only attempted in the presence of

sufficient data from eligible trials (>3 studies) and in the absence

of substantial heterogeneity. Otherwise a comprehensive system-

atic review was performed to outline the current evidence from

included trials. In accordance to the assessment of heterogeneity,

we applied a fixed- or random-effects model.

Subgroup analysis and investigation of heterogeneity

If case of sufficient number of studies (i.e.>

= 3 RCT), subgroup

analysis was performed for:

- type of cardiac procedures (i.e. CABG versus valve surgery; emer-

gency vs. non-emergency cardiac surgery),

- statin agent used,

- duration of statin intake prior to surgery (over or less than 21

days),

Sub-grouping was used to assess statistical heterogeneity. Aspects

of study population, outcome measurement and quality of studies

were taken into account.

Sensitivity analysis

Sensitivity analysis was performed to estimate differences of treat-

ment effects between trials of low, moderate or high methodolog-

ical quality.

R E S U L T S



Description of studies

See: Characteristics of included studies; Characteristics of

excluded studies; Characteristics of studies awaiting classification;

Characteristics of ongoing studies.

Results of the search

Electronic search on MEDLINE, CENTRAL and EMBASE re-

trieved 1777 references, 1329 records remained after de-duplica-

tion. After review of titles and abstracts, 1269 references were ex-

cluded as being not relevant. From the remaining 60 references,

44 studies (44 references) were excluded after full-text evaluation

(Characteristics of excluded studies) and three studies (three ref-

erences) are awaiting classification.

Search for ongoing trials revealed four studies. One record was

found to be a completed study that was already included as sec-

ond reference (Song 2008). Therefore, three studies are listed as

ongoing (Characteristics of ongoing studies).

Searching conference indices located four abstracts. The authors

of two abstracts were contacted by email but definitive in- or exclu-

sion could not be decided since answers of authors are still pending

and therefore, classification is awaiting (Antoniades 2010; Song

2007), giving a total of five studies (five references) awaiting classi-

fication (Characteristics of studies awaiting classification). Results

of the included trial from Patti et al (Patti 2006) were presented

twice during conferences of which the abstracts were found and

added as additional references.

As a result, 11 studies (16 references) met the inclusion criteria

(Figure 1).

Figure 1. Study flow diagram.



Included studies

A total of 11 studies was included into the analysis (reported in

16 references).

Design

All included studies were randomised controlled trials with a mean

study duration of 16 months (median duration 17 months). The

original papers published from 1999 to 2010 were available in

full-text versions.

Sample sizes

The number of participants recruited in the 11 included studies

varied from 20 (Florens 2001) to 200 (Mannacio 2008; Patti

2006) with a total sample size of 984 patients. Of those, 495

patients (50.3%) were treated with statins and 489 (49.7%) served

as controls prior to cardiac surgery.

Setting

Four trials reported the setting of the study and were all carried out

at a university hospital. Three of these four studies were conducted

by the same investigator group in Rome, Italy (Chello 2006; Patti

2006, Spadaccio 2010) and one was carried out in Valladolid,

Spain (Tamayo 2009). The geographical location of the remaining

trials was inferred from the institution of the primary author. Three

studies were conducted in Europe, three trials in Asia and one

study in South America.

Participants

The total group of participants consisted of 288 women (28.5%)

and 704 men (71.5%) with a mean age of 64.6±9.0 years in the

statin treatment arm and a mean age of 65.5±9.3 years in the con-

trol arm. Only two studies included patients undergoing a treat-

ment other than isolated CABG operations (n: 220; 22.4% of all

patients) (Patti 2006; Florens 2001), and two trials focused on the

treatment effects in patients undergoing off-pump CABG proce-

dures (Ji 2009; Song 2008). The average preoperative left ventric-

ular ejection fraction was 54.2±11.1% for patients taking statins

and 53.4±10.7% for patients in the control group. The overall

incidence of MI (26.4% vs. 24.6%), diabetes (32.6% vs. 37.9%),

hypertension (50.5% vs. 48.9%) and use of beta-blockers (64.1%

vs. 58.9%) prior to surgery were comparable among treatment

groups.

Interventions

In the majority of studies, statin treatment comprised of ator-

vastatin therapy (n=6 trials) with dosages of either 20 mg or 40

mg. Simvastatin was used in two trials (20 mg), and the study

medication was fluvastatin (80 mg), rosuvastatin (20 mg), and

pravastatin (40 mg) in one study, respectively. A comparison with

placebo was carried out in six trials, whereas five studies compared

patients receiving preoperative statin treatment to a statin naive

control group without placebo therapy. The duration of preop-

erative intake of the study medication varied from the evening

before surgery (Florens 2001) to four weeks before the operation

(Christenson 1999). Only three trials reported a post-operative

re-initiation regimen of statin therapy (Patti 2006; Song 2008;

Caorsi 2008).

Outcomes

The primary outcome short-term post-operative mortality (i.e. in-

hospital or 30-day mortality) was reported in seven studies, repre-

senting a total of 675 patients (68,6% of total patients). In these

studies, mortality rates were assessed in terms of in-hospital mor-

tality in five studies and 30 day-mortality in two studies. Nine

of eleven trials (n=897; 91.1%) analysed the incidence of post-

operative myocardial infarctions based on different definitions,

while eight trials provided data about post-operative AF (n=841;

85,5%). Two studies explicitly reported on new onset AF includ-

ing a total of 324 patients (32.9%), whereas the remainder did not

clearly define the kind of AF. The incidence of stroke was avail-

able in four studies (n=374; 38.0%), and data was retrieved from

one further study after contacting the author by email (Florens

2001). Appearance of post-operative renal failure was an exclusion

criterion in one study (Ji 2009), and data related to the incidence

of post-operative renal failure was obtained from a total of four

studies (n=367; 37.3%). Data on the length of stay on the ICU

and length of stay in the hospital were reported by seven (n=521;

52.9%) and eight studies (n=877; 89.1%), respectively. Detailed

information with regard to adverse side effects by the statin pre-

treatment was reported in only three studies (n=86; 8.7%).

Excluded studies

Although search criteria were designed to find exclusively ran-

domised controlled trials, retrospective and non-randomised stud-

ies were also identified in our literature search. Furthermore, stud-

ies reporting outcomes after post-operative statin therapy did

not meet the desired inclusion criteria. Trials accepting co-inter-

ventions to statin treatment or comparing different statin doses

without comparing them to statin-naive patients (control groups)

undergoing cardiac surgery were not considered for final analy-

sis. Finally, trials investigating endpoints other than the our pri-

ori defined outcomes were excluded (Characteristics of excluded

studies).

Ongoing studies



Search of ongoing studies found three potentially eligible ongoing

trials. Two of these studies (Billings 2009; Kindo 2008) were in the

recruiting phase at the time of this review and will be completed

at the earliest in December 2011 (information current as May

4, 2011). The status of one study was unknown at the time of

writing this review (Bellomo 2008). Two studies are focusing on

the statin impact on post-operative renal insufficiency (Bellomo

2008; Billings 2009) and one is aiming to investigate the statin

effects in patients undergoing aortic valve replacement surgery

(Kindo 2008).

Studies awaiting classification

Two potentially eligible studies were found after search on con-

ference indices (Antoniades 2010; Song 2007). Authors of both

studies were contacted by email to clarify the inclusion criteria.

Definite status of three further trials was checked by contacting

authors by email since more information was requested regard-

ing potential duplicate publication of one study cohort (Chello

2005; Chello 2007; Coccia 2007). At the date of publication of

this review none of the investigators of the above mentioned trials

responded resulting in exclusion of the studies until further eval-

uation is possible.

Risk of bias

Risk of bias in included studies

Potential sources of bias are summarised in Figure 2 and Figure 3.

In summary, there was low risk of bias other than random sequence

generation allocation (<45% of trials use this method) and lack of

allocation concealment (<20% of trials ensured this).

Figure 2. Methodological quality graph: review authors’ judgements about each methodological quality

item presented as percentages across all included studies.



Figure 3. Methodological quality summary: review authors’ judgements about each methodological quality

item for each included study.



Allocation

Risk of bias was reduced in two studies by allocation concealment

and in five studies the random sequence was adequately described.

In contrast, allocation concealment and random sequence genera-

tion were not clearly described in nine and six studies, respectively,

with inherent risk for selection bias.

Blinding

In nine of the 11 included studies patients and investigators were

blinded to treatment arms. Blinding was not performed in one

study, whereas one study failed to adequately report blinding fash-

ion. With regard to potential blinding of patients, care givers and

assessors, three studies were triple-blinded, four studies double-

blinded and two were single-blinded.

Incomplete outcome data

In one study the authors did not clearly address the reporting of

incomplete outcome data (Christenson 1999).

Selective reporting

One trial that did not address incomplete outcome data was judged

to be affected by selective reporting (Christenson 1999).

Other potential sources of bias

Four studies explained the method used for the sequence genera-

tion, whereas seven trials performed a sample size calculation prior

the start of the study. ITT analysis was used in only four studies

and one trial was supported by a commercial grant (Christenson

1999). Visual assessment of funnel plots for publication bias was

performed for the effect measurements with significant statin treat-

ment effects (i.e. AF, length of stay on ICU and in hospital) and

failed to reveal a substantial asymmetry around the mean OR or

WMD. Similarly, no significant publication bias was confirmed

for analysed effect measures using Egger’s weighted regression anal-

ysis (AF: -0.006; 95% CI: -0.581 to 0.570; p=0.98; Length of

stay on ICU: -2.73; 95% CI: -7,562 to 2,104; p=0.206; Length

of stay in hospital: 1,804 95% CI: -3,320 to 6,928; p=0.422).

In the absence of significant publication bias a correction using

the Trim-and-Fill method was not performed. Of the seven trials

that performed a sample size calculation on the primary outcome

measure, one failed to demonstrate a significant difference among

investigated treatment groups; similarly, one of four studies that

did not report a sample size calculation revealed a non-significant

result. Therefore, these studies are at risk for type II error for their

primary endpoint.

Effects of interventions

See: Summary of findings for the main comparison Statin

therapy for patients undergoing cardiac surgery

Short-term mortality

Seven trials reported on short-term mortality (i.e. in-hospital or

30-day mortality) including a total of 675 participants (68.6%

of total patients) during a mean post-operative follow-up of 16.4

days. Deaths occurred only in one trial with two deaths in both

the statin (0.6%) and control (0.6%) groups (OR 0.98, 95%-CI:

0.14 to 7.1; p=0.98). Thus, assessment of heterogeneity was not

applicable. Sub-group analysis was not performed in the presence

of minimal event data.

Myocardial infarction

Nine trials with 897 participants (91.1% of total patients) reported

data on MI (Analysis 1.2) during a mean post-operative follow-up

of 18.9 days. There were six MI events in the statin (1.3%) and

12 in the control group (2.7%). No heterogeneity was observed

among studies. Pooled analysis using a fixed- effect model revealed

a 48% odds reduction but failed to reach statistical relevance (OR

0.52, 95%-CI: 0.2 to 1.3; p=0.16).

Subgroup analysis of studies investigating on-pump CABG pro-

cedures included seven studies with a total of 753 participants

(Analysis 3.1). The treatment effect of statins on MI in the on-

pump subgroup was accentuated (OR 0.39; 95%-CI: 0.14 to 1.12:

p=0.08) when compared to the overall result. In contrast, pooled

analysis of trials that included only elective cardiac surgery pro-

cedures in a total of 800 participants (Analysis 4.1) revealed a re-

duction of the statin treatment effect for MI (OR 0.85; 95%-CI:

0.29 to 2.74; p=0.77). Neither analysis of studies with a preoper-

ative statin therapy for longer than 21 days or analysis of studies

utilizing atorvastatin (Analysis 5.1 and Analysis 6.1) resulted in a

significant reduction in the odds for MI.

Atrial fibrillation

Eight studies provided data on the incidence of AF from a total

of 841 patients (85.5% of total patients) (Analysis 1.3) during a

mean length of follow-up of 22.8 days. Eighty events (19%) were

observed in the statin group and 149 events (35.6%) were observed

in the control group resulting in an odds reduction of 60% after

pooled analysis with a fixed-effect model (OR 0.40; 95%-CI: 0.29

to 0.55; p<0.01). The overall number needed to treat (NNT) was

seven. All individual studies reported an odds ratio of less than 1.0

favouring statin pretreatment over control intervention without

heterogeneity among trials.



In addition, the aforementioned pooled treatment effect favouring

statin therapy was matched by subgroup analysis of patients un-

dergoing only CABG and only elective procedures (Analysis 2.2;

Analysis 4.2). The beneficial statin treatment effect persisted after

subgroup analysis in patients undergoing on-pump CABG pro-

cedures (seven studies with 717 patients; Analysis 3.2), receiving

atorvastatin (five studies with 554 participants; Analysis 5.2) and

taking statins over a period of more than 21 days before surgery

(four studies with 258 participants; Analysis 6.2).

Stroke

Five studies reported data on the incidence of stroke in a total of

374 patients (38.0% of total patients; Analysis 1.4) with two events

(1.1%) in the statin group and three events (1.6%) in the control

group (OR 0.7; 95%-CI: 0.14 to 3.63; p=0.67). No heterogeneity

was detected among studies. Analysis of subgroups failed to reveal

any treatment effect for stroke in CABG patients undergoing elec-

tive or on-pump surgery or receiving atorvastatin (Analysis 2.3;

Analysis 3.3; Analysis 4.3; Analysis 5.3). Pooled treatment effects

of two studies with a preoperative statin therapy for more than 21

days were not estimable due to missing clinical events (Analysis

6.4).

Renal failure

Four trials reported the incidence of renal failure during a mean

post-operative follow-up period of 12.2 days in a total of 367

participants (37.3% of total patients; Analysis 1.5). The incidence

of renal failure was 3.2% in the statin group compared to 7.1%

in the control group. Two of the included studies demonstrated a

beneficial effect of statin therapy with odds ratios of 0.29 (95%-CI:

0.07 to 1.21) and 0.33 (95%-CI: 0.03 to 3.19), respectively. The

2 remaining studies could not demonstrate a difference between

treatment groups. Due to the higher weight of trials favouring

statin therapy, pooled analysis using a fixed-effect model showed

that statin treatment led to a 59% reduction of the odds of renal

failure (OR 0.41; 95%-CI: 0.15 to 1.12; p=0,08) with a trend

towards statistical relevance.

Similarly, subgroup analysis did not reveal a relevant treatment ef-

fect among groups in patients undergoing CABG (including elec-

tive or on-pump CABG), or in groups treated with atorvastatin

or those receiving statins over a period of more than 21 days be-

fore surgery (Analysis 2.4; Analysis 3.4; Analysis 4.4; Analysis 5.4;

Analysis 6.3). No significant heterogeneity among studies was de-

tected.

Length of ICU stay ICU

Seven trials analysed the length of stay on the ICU after cardiac

surgery in a total of 521 participants (52.9% of total patients;

Analysis 1.6). Mean length of stay on the ICU was 48±24 hours in

the statin pretreated group and 48±21 hours in controls. Analysis

of weighted mean difference using a fixed-effect model showed a

significant reduction of ICU stay that favoured statin over control

therapy (WMD: -3.39 hours; 95%-CI: -5.77 to -1.01; p=0.005),

with statin pretreated patients being discharged from the ICU

3.39 hours earlier compared to statin naive patients. No significant

heterogeneity was observed among studies.

Similarly, the significant reduction in WMD of ICU length of stay

persisted after subgroup analysis of patients undergoing CABG

(including elective or on-pump CABG; Analysis 2.5; Analysis 3.5;

Analysis 4.5) or that were treated with statins over a period of more

than 21 days before surgery (Analysis 5.5), but with borderlines

reduction of ICU stay in patients treated with atorvastatin only (p=

0.06) (Analysis 6.4). No significant heterogeneity among studies

of subgroup analysis was detected.

Length of stay in the hospital

Eight studies recorded the length of stay in the hospital (days) in

a total of 877 participants (89.1% of total patients; Analysis 1.7)

with a mean length of hospital stay of 8.5±1.8 days in the statin

pretreated group and 9.0±1.9 in controls.

Significant heterogeneity was observed among included studies

with an I2 of 64% (p=0.008). Analysis of WMD using a random-

effects model demonstrated a reduced length of stay in hospital

in statin pretreated patients (WMD: -0.48 days; 95%-CI: -0.85

to -0.11: p=0.01) compared to the control group. The significant

reduction in WMD of hospital length favouring statin therapy

persisted after subgroup analysis of patients undergoing CABG

(including elective or on-pump CABG; Analysis 2.6; Analysis 3.6;

Analysis 4.6) or in patients treated with atorvastatin only (Analysis

5.6), but was not observed in studies that treated patients with

statins for a period of over 21 days before surgery (Analysis 6.5).

Statin adverse effects

Three studies provided information about the incidence of ad-

verse effects related to statin treatment in a total of 86 partic-

ipants (17.4% of all included participants treated with statins),

even though clear definitions of recorded side effects were not re-

ported. No adverse events were noted in either of the three trials.

The used statin drugs were atorvastatin in a total of 65 patients of

two trials (Chello 2006; Spadaccio 2010) and pravastatin in the

remaining 21 patients of one trial (Caorsi 2008).

Sensitivity analysis

Sensitivity analyses for all outcome measures were performed for

studies with and without a clear blinding process, a adequate se-

quence generation and an allocation concealment. However, no

significant differences were found after sensitivity analysis and

when compared to the results of effect measures.



D I S C U S S I O N

Summary of main results

The present systematic review included 11 RCTs that summa-

rized data on pre-defined endpoints from a total sample size of

984 cardiac surgery patients (Summary of findings for the main

comparison). Pre-operative statin therapy was associated with a

significant reduction for the odds of AF after cardiac surgery, sug-

gesting a beneficial effects for a pre-operative statin treatment when

compared to control. In addition, patients with a pre-operative

statin medication had a significantly reduced length of stay in

ICU and in the hospital when compared to statin naive patients.

Both findings might be driven by the higher incidence of AF in

statin-untreated patients which is known to be associated to post-

operative complications and prolonged duration of hospital stay.

Importantly, for length of hospital stay, significant heterogeneity

was observed among studies. Pooled analysis of treatment effects

for the endpoint renal failure and MI suggest a potential protec-

tive effect of a pre-operative statin therapy that, however, failed to

reach statistical difference when compared to controls. Similarly,

no differences in treatment effects was observed with regard to

post-operative short-term mortality and stroke among statin pre-

treated or naive patients. Safety endpoints of a pre-operative statin

therapy were rarely reported by investigators with no adverse statin

event observed. Although these findings might implicate the safety

of a pre-operative statin therapy the amount of available infor-

mation about adverse statin actions from included trials is clearly

insufficient.

Overall completeness and applicability ofevidence

This review was based on a limited number of trials with a small

numbers of mainly male patients aged in their mid 60s, mostly

conducted in industrialised countries. From a demographic per-

spective the study population is a representative cohort that is

commonly referred to cardiac surgical procedures in western, de-

veloped countries, especially with regard to the distribution of

gender, age and co-morbidities. Although the type of statin, statin

dose and timing of administration was highly variable among in-

cluded trials, all implemented statin therapy regimens used by the

studies are transferable to the preoperative routine use of statins

in patients scheduled for cardiac surgery. Of note, only three tri-

als provided information about a rigorous post-operative re-initi-

ation regimen of statins in recruited patients. Thus, the potential

impact of a strict and early statin re-initiation on post-operative

outcomes after cardiac surgery still remains unclear. All analysed

clinical outcome variables were addressed by at least four trials

with a minimum sample size of 367 patients. Consequently, the

results of these trials and, moreover, the pooled data analyses from

the total patient cohort, appears to be representative of the routine

patients cohort that is scheduled for a elective cardiac surgery pro-

cedures. Nonetheless, the predominant operation performed in

the included studies was CABG with the use of cardiopulmonary

bypass (n=658; 66.9% of total patients). Thus, extrapolation of

the above mentioned findings is not advisable for patient popu-

lations other than on-pump CABG (such as patients undergoing

valve or aortic surgery) until further evidence from RCTs is made

available.

Quality of the evidence

Nine of the 11 included studies adequately addressed the blinding

fashion of their trial, and six trials implemented a randomization

of statin treatment against a placebo medication while the remain-

ing five studies compared statin pretreated against statin naive pa-

tients. Only two trials explicitly reported allocation concealment

and five studies employed an adequate allocation sequence gener-

ation. Thus, the overall quality of evidence from included studies

is limited and restricts the overall validity of our final conclusion.

Methodologically, the quality of the overall evidence derived from

included studies is further limited by the fact that only four trials

used an intention-to-treat analysis and only seven studies reported

adequate sample size calculation in order to obtain a sufficient

power for the measured outcome in their study population. The

total number of included patients was relatively low and the overall

population consisted predominantly of males aged 60 to 70 years

with a remarkable low mortality rate of less than 1%. Moreover,

all sample size calculations were based on primary outcome mea-

sures other than mortality. While 10 studies addressed incomplete

outcome data and were classified as free of selective reporting, only

three trials provided information about adverse events of statins or

adequate safety outcomes. Regarding sponsorship by industries,

only one study reported the support by a grant of a pharmaceutical

company.

A cost-effectiveness analysis of statins for patients undergoing car-

diac surgery could not be performed from the available data since

no study reported data relevant to these aspects. Taking into ac-

count the treatment effect of statins with regard to post-operative

AF and the association of a preoperative statin therapy to a reduced

length of stay on the ICU and the hospital for cardiac surgery pa-

tients, a cost-effectiveness evaluation of the statin treatment effect

appears justified and reasonable and should be addressed in future

larger-scaled RCTs.

Potential biases in the review process

The applied methods and predefined criteria for the inclusion of

trials into this review included clearly delimited aspects of study

design and reporting of relevant outcomes. Due to the extensive

literature search strategy with generation of well-defined key words



and employment of a sensitive human filter for RCTs the potential

risk for missing eligible RCT studies that may have assessed the

effect of statin therapy on outcomes after cardiac surgical proce-

dures seems minimal, but cannot be definitely excluded. All in-

cluded trials added data for at least one outcome measure in com-

pliance with the predefined criteria for the subsequent analysis.

In addition, the primary outcome in terms of short-term post-

operative mortality was well defined and was assessed by most of

the included studies. However, the exact definitions of outcome

measures such as detection of post-operative AF, MI, and renal

failure were inconsistent among included studies, but generally

followed common definitions for these endpoints after cardiac sur-

gical procedures. Unfortunately, guideline-driven definitions for

desired endpoints, especially for MI and renal failure, were rarely

implemented among included studies at this stage of the review,

but will potentially become available as soon as more data from

larger RCTs are provided. Despite our multiple attempts to obtain

additional or missing information of potentially relevant studies

directly from the corresponding authors, not all desired data could

be retrieved with unknown implications for potential bias. Fur-

ther sources of potential bias were sought to be limited by rigorous

assessment of all included studies (Figure 2 and Figure 3). Meta-

regression to investigate the impact of relevant covariates of studies

on the statin effect estimates was not performed in the absence

of an adequate number of studies (<10 studies per analysed out-

come). Finally, inadequate blinding of physicians and study per-

sonal among included studies and the use of a placebo treatment

versus no placebo (detection and performance bias) might have

also conferred to a additional risk of bias for the investigated effect

measures (Figure 3).

Agreements and disagreements with otherstudies or reviews

The impact of a pre-procedural statin therapy prior to percuta-

neous coronary interventions, coronary artery bypass graftings and

noncardiac procedures on clinical outcomes was investigated by

Wichester et al. in a recent systematic review with meta-analysis

(Winchester 2010). Statin pre-treatment had no impact on mor-

tality rates in patients undergoing CABG (OR 0.98; 95%-CI:

0.14 to 6.82), a finding that was based on the result of only one

study. Furthermore, pooled analysis of three placebo-controlled

trials reporting the impact of statins on post-operative myocardial

infarction revealed a non-significant trend favouring statin treat-

ment (OR 0.7, 95%-CI: 0.21 to 2.36; p=0.787), a finding that

was also resembled in our findings. Similarly, the authors revealed

a significant beneficial effect of statin therapy before surgery on

the incidence of post-operative AF (OR 0.54; 95%-CI: 0.43 to

0.68; p<0.0001).

Another meta-analysis aimed to assess the impact of pre-operative

statin therapy on relevant clinical outcomes after cardiac surgery

and included more than 30,000 participants (Liakopoulos 2008)

from predominantly observational trials. Statin therapy was asso-

ciated with a reduced early all-cause mortality (OR 0.57; 95%-

CI: 0.49 to 0.67; p<0.001), incidence of post-operative AF (OR

0.67; 95%-CI: 0.51 to 0.88; p=0.004) and stroke (OR 0.74; 95%-

CI: 0.6 to 0.91; p=0.004), but statin treatment had no effect on

post-operative MI or renal failure. However, this analysis added

up data from only three small randomized controlled trials and

16 observational studies, with five large observational reports in-

cluding over 6,400 participants for each endpoint. This systematic

review was performed in accordance to the guidelines for quality

of reporting of meta-analysis with pre-specified definitions of out-

come variables. A more recent systematic review by the same group

was aimed to investigate the impact of a statin pretreatment on

the incidence of new-onset AF after cardiac surgery (Liakopoulos

2009) from thirteen studies (three randomized controlled trials,

10 observational trials) summarising data from a total of 7855

cardiac surgery patients. Preoperative statin use resulted in a 34%

odds reduction for new-onset AF (OR: 0.66; 95%-CI: 0.51 to

0.84; p<0.001) after surgery. Relevant publication bias and an

unequal distribution of confounding variables favoring patients

treated with statins (i.e. beta-blocker therapy) were identified in

this analysis. Nevertheless, the beneficial actions of statins on AF

persisted also after pooled analysis of risk-adjusted treatment ef-

fects from randomized controlled trials and observational trials

(OR: 0.66; 95%-CI: 0.48 to 0.89; p<0.01).

Two further reviews report lower mortality rates for patients receiv-

ing statin therapy preoperatively. However, the results were predi-

cated mainly on retrospective studies both in the review conducted

by Takagi et al. (OR 0.76; 95%-CI: 0.64 to 0.90) and Hindler et

al. (OR 0.62; 95%-CI: 0.48 to 0.79), respectively (Hindler 2006;

Takagi 2009). But in contrast to other meta-analyses that describe

a beneficial or no clear effect of statin therapy on the incidence

of post-operative MI, Hindler et al. concluded that statin treat-

ment was linked to an increase in the odds for MI compared to

control (OR 1.27; 95%-CI: 1.01 to 1.6; p=0.04). An explanation

for this observation may be found in the heterogeneous defini-

tions of myocardial infarction and the heterogeneity among the

included studies. Likewise, the potential protective effect of statins

against post-operative AF compared to control intervention could

not be confirmed by a meta-analysis performed by Yin et al. (OR

0.85; 95%-CI: 0.66 to 1.09; Yin 2010). In sharp contrast to our

review where only RCTs were analysed, the result found by Yin

et al. (Yin 2010) was driven from six retrospective trials with a

total of more than 10,000 participants, but again with significant

heterogeneity among included studies. Similar to the findings of

our meta-analysis, Chen et al. found a linkage between statin in-

take and a shorter in-hospital stay after cardiac surgery in a pooled

analysis of six RCTs including 651 participants (weighted mean

difference -0.66, 95%-CI: -1.01 to -0.30) in addition to a re-

duction of post-operative AF (RR 0.57; 95%-CI: 0.45 to 0.72;

Chen 2010). Although some observations made from the recent



systematic (Winchester 2010; Yin 2010) are in close agreement to

the findings of the present analyses with regard to the impact of

preoperative statin use on post-CABG short-term mortality, AF,

and MI the current review sums up the evidence from more RCTs

with focus on additional clinical relevant endpoints such as ICU

and hospital length of stay, renal failure and stroke. Additionaly,

various subgroup analyses were implemented to detect potential

patient cohorts that may profit the most from a statin therapy

before surgery.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

The cumulative evidence from eleven RCTs that were included

in the present systematic review with meta-analysis demonstrates

that a pre-operative statin therapy is beneficial for patients under-

going cardiac surgical procedures in terms of a reduction of post-

operative AF and a potential benefit in terms of a shorter stay both

on the ICU and in the hospital. Although a pre-operative statin

therapy was found to be associated with lower incidence for MI

and renal failure, these results did failed to reach statistical sig-

nificance. A significant treatment effect of a pre-operative statin

therapy on short-term mortality and stroke after cardiac surgery

could not be detected. Only a few trials reported on statin side-

effects, with no event occurring in either study. Thus, the bene-

ficial effects of statins presumably overbalances the inherent risks

that are associated with a statin pre-treatment. Since the majority

of studies included into the analysis of this review assessed the ef-

fects of atorvastatin on patients undergoing predominantly elective

CABG procedures, the extrapolation of the findings to patients

treated with different types of statins and referred to operations

other than CABG must be handled with caution until further ev-

idence from RCTs is available. Until then, empirical use of statins

for all patients undergoing cardiac surgery seems premature, un-

til further evidence from future RCTs is sufficiently accumulated.

Nonetheless, it appears reasonable and in compliance with existing

guidelines to advocate an intensified preoperative statin treatment,

followed by a rigorous post-operative re-initiation regimen, in all

hyperlipaemic patients with multiple cardiac risks and coronary

heart disease scheduled for cardiac surgery.

Implications for research

As the impact of statin treatment on clinical outcomes in car-

diac surgery is mainly assessed in patients scheduled for routine

CABG procedures, there is only sparse evidence for a benefit of

a statin therapy for high risk patient subgroups and those under-

going other cardiac procedures (for example valvular operations

or combined procedures). In light of an increasing proportion of

patients referred to cardiac surgery presenting with multiple co-

morbidites that potentially precipitate the development of adverse

outcomes after surgery, the pre-treatment with statins needs to be

investigated in these high-risk patient cohorts. Moreover, studies

comparing the different types of statins and dose regimens before

and after surgery are highly desirable since new statin agents have

emerged that may or may not offer further or more beneficial ef-

fects. Therefore, the question for the most beneficial statin medi-

cation and for the most effective timing of administration before

surgery remains unanswered . This is even more important when

taking into account that recent evidence suggests improved clin-

ical outcomes (Di 2009) with a short-term and high-dose statin

treatment (recapture therapy) prior to percutaneous coronary in-

terventions (PCI) in patients that are on a chronic statin therapy;

a finding that may have highly relevant clinical implications also

for the improvement of outcomes of cardiac surgery patients.

Finally, compliance rate to statin treatment and cost-effectiveness

need to be evaluated for statin therapy in cardiac surgery since

benefits, harms and costs should be balanced for the specific pa-

tient subsets. It is therefore necessary that future studies also aim

at examining the costs/ effectiveness ratio in order to estimate the

objective profits of statin medication before cardiac surgery proce-

dures. Moreover, patients´ quality of life should be implemented

in upcoming trials since this represent a major aspect for the co-

herence to chronic medical therapy.

A C K N O W L E D G E M E N T S

We would like to thank Nicole Ackermann, Trials Search Co-or-

dinator of the Cochrane Heart Group (London, UK), for assisting

us with the literature research for this review.



R E F E R E N C E S

References to studies included in this review

Berkan 2009 {published data only}

Berkan O, Katrancioglu N, Ozker E, Ozerdem G, Bakici Z,

Yilmaz MB. Reduced P-selectin in hearts pretreated with

fluvastatin: a novel benefit for patients undergoing open

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Caorsi 2008 {published data only}

Caorsi C, Pineda F, Munoz C. Pravastatin immunomodulates

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Chello 2006 {published data only}

Chello M, Patti G, Candura D, Mastrobuoni S, Di

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Christenson 1999 {published data only}

Christenson JT. Preoperative lipid control with simvastatin

protects coronary artery bypass from obstructive graft

disease. The American journal of cardiology 2001;88(8):

896–9. [PUBMED: 11676957]∗ Christenson JT. Preoperative lipid-control with simvastatin

reduces the risk of postoperative thrombocytosis and

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European Association for Cardio-thoracic Surgery 1999;15(4):

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Florens E, Salvi S, Peynet J, Elbim C, Mallat Z, Bel A,

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Ji Q, Mei Y, Wang X, Sun Y, Feng J, Cai J, et al.Effect

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Mannacio 2008 {published data only}

Mannacio VA, Iorio D, De Amicis V, Di Lello F, Musumeci

F. Effect of rosuvastatin pretreatment on myocardial damage

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Candura C, Chello M, Lusini M, Patti G, Barbato R, Di

Sciascio G, Covino E. A randomised trial of atorvastatin

for reduction of myocardial damage during CABG: The

ARMYDA-4 study (atorvastatin for reduction of myocardial

damage). Interactive CardioVascular and Thoracic Surgery;

Abstracts for EACTS congress 2008; Vol. 7.∗ Patti G, Chello M, Candura D, Pasceri V, D’Ambrosio

A, Covino E, et al.Randomized trial of atorvastatin for

reduction of postoperative atrial fibrillation in patients

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Patti G, Chello M, Candura D, Pasceri V, D’ambrosio A,

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Song 2008 {published data only}

On YK. Atorvastatin for prevention of postoperative atrial

fibrillation after off-pump coronary artery bypass grafting

surgery. www.clinicaltrials.gov last update January 27,

2008. [: NCT000611143]∗ Song YB, On YK, Kim JH, Shin DH, Kim JS, Sung

J, et al.The effects of atorvastatin on the occurrence of

postoperative atrial fibrillation after off-pump coronary

artery bypass grafting surgery. American heart journal 2008;

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Spadaccio 2010 {published data only}

Spadaccio C, Pollari F, Casacalenda A, Alfano G, Genovese

J, Covino E, et al.Atorvastatin increases the number

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Tamayo 2009 {published data only}

Tamayo E, Alonso O, Alvarez FJ, Castrodeza J, Florez S, di

Stefano S. Effetcs of simvastatin on acute-phase protein

levels after cardiac surgery [Efecto de la simvastatina en la

concentration de las proteinas de fase aguda despues de la

cirugia cardiaca]. Medicina clinica 2008;130(20):773–5.

[PUBMED: 18579030]∗ TAMAYO E, ALVAREZ FJ, ALONSO O,

BUSTAMANTE R, CASTRODEZA J, SORIA S, et

al.Effects of simvastatin on systemic inflammatory responses

after cardiopulmonary bypass. The Journal of cardiovascular

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Ali IS, Buth KJ. Preoperative statin use and in-hospital

outcomes following heart surgery in patients with unstable

angina. European journal of cardio-thoracic surgery : official

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Barbir 1994 {published data only}

Barbir M, Hunt BJ, Galloway D, Taylor A, Ilsley C,

Mitchell A, et al.A randomized pilot trial of low-dose

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Borger 2010 {published data only}

Borger MA, Seeburger J, Walther T, Borger F, Rastan A,

Doenst T, et al.Effect of preoperative statin therapy on

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Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries

SE, Montgomery HE. Statin therapy and the acute

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Cannon CP, Braunwald E, McCabe CH, Rader DJ,

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C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Berkan 2009

Methods study design: RCT

total study duration: not reported

Participants inclusion criteria: primary elective CABG

total number: 46

Interventions statin type: fluvastatin, n=23

dose: 80 mg/day

length of preoperative statin exposure: 3 weeks

control-group: placebo, n=23

Outcomes mortality:

myocardial infarction: +

atrial fibrillation:

stroke:

renal failure:

length of stay on ICU: +

length of stay in hospital: +

other key-outcomes: sP-selectin, intraop. IABP, cTnI

Notes

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection

bias)

Low risk randomized into two groups (1:1)

Allocation concealment (selection bias) Unclear risk “blinding to drug assignment”

Blinding (performance bias and detection

bias)

All outcomes

Low risk “both patients and physicians were blinded

to the drug assignment”

Incomplete outcome data (attrition bias)

All outcomes

Low risk no incomplete outcome data

Selective reporting (reporting bias) Low risk study protocol not available, but report in-

cludes all expected outcomes

Other bias Low risk overall, this study seems to be free of other

bias



Berkan 2009 (Continued)

Sample size calculation Low risk investigators performed a sample size cal-

culation

analysis of intention-to-treat Low risk all patients completed study as allocated

ethical approval Low risk study ethically approved

Free of commercial funding? Low risk no funding by a company

Caorsi 2008



Participants inclusion criteria: elective, on-pump CABG

total number: 43

Interventions statin type: pravastatin, n=21

dose: 40 mg/day + 40 mg 1h after CPB

length of preoperative statin exposure: 48 h

control-group: control, n=22

Outcomes mortality: -

myocardial infarction: -

atrial fibrillation: +

stroke: -

renal failure: -

length of stay on ICU: -

length of stay in hospital: -

other key-outcomes: IL-6/-8, TNF-a, CRP

Notes atrial fibrillation as desired outcome data included after discussion

Risk of bias



bias)

Unclear risk not reported

Allocation concealment (selection bias) Unclear risk not reported


bias)

All outcomes



All outcomes




Caorsi 2008 (Continued)



Other bias Unclear risk e.g. lacking study protocol

Sample size calculation High risk investigators performed no sample size cal-

culation

analysis of intention-to-treat Unclear risk no clear information about intention-to-

treat analysis



Chello 2006


total study duration: 05.2003-09.2004

Participants inclusion criteria: elective CABG

total number: 40

Interventions statin type: atorvastatin, n=20

dose: 20 mg/day



Outcomes mortality:+



stroke: +

renal failure: +



other key-outcomes: SIRS score, neutrophil isolation, CD11b expression, IL-6/-8, TNF-

a, hemodynamics

Notes

Risk of bias



bias)




Chello 2006 (Continued)



bias)

All outcomes

Low risk both patients and physicians were blinded


All outcomes





bias

Sample size calculation Low risk “we hypothesized a similar effect by statin

therapy after CABG, a population of 40

pts. (20 in each group) would be needed to

detect this difference with an alpha of .05

and a power of .80”


treat analysis



Christenson 1999



Participants inclusion criteria: CABG and hypercholesteremia

total number: 77

Interventions statin type: simvastatin, n=40

dose: 20 mg/day



Outcomes mortality: +


atrial fibrillation: -

stroke: +

renal failure: +





Christenson 1999 (Continued)

other key-outcomes: serum-lipids, thrombocytosis, thrombotic complications

Notes

Risk of bias



bias)

Unclear risk “patients were randomly assigned either to

proceed directly to surgery (...) or to un-

dergo a 4 week preoperative treatment with

simvastatin”

Allocation concealment (selection bias) Unclear risk “assigned either to proceed directly”


bias)

All outcomes

Low risk “surgeons, who were both unaware of the

patients group identity, performed all op-

erations”


All outcomes

High risk What about the non-elective procedures?

Selective reporting (reporting bias) Unclear risk all outcomes, but not all patients reported

(non-electives)

Other bias Unclear risk e.g. lacking information about non-elective

patients


culation


treat analysis


Free of commercial funding? High risk Merck Sharp and Dohme-Chibret SA

Florens 2001



Participants inclusion criteria: various cardiac operations with CPB

total number: 20


dose: 40 mg/day



Florens 2001 (Continued)

length of preoperative statin exposure: ~12 h




atrial fibrillation: -

stroke: -(/+) (Data retrieved after contacting author by email)

renal failure: -


length of stay in hospital: -

other key-outcomes: IL-6/-8, CD11b, sICAM-1, lactoferrin, NF-kB

Notes post-operative myocardial infarction included as desired outcome after discussion

Risk of bias



bias)




bias)

All outcomes

Low risk “All investigators involved in clinical care

and biochemical assays were blinded as to

the patient group.”


All outcomes


Selective reporting (reporting bias) Low risk study protocol not available, but all ex-

pected outcome data reported


bias


culation


treat analysis





Ji 2009



Participants inclusion criteria:elective isolated OPCAB

total number: 140


dose: 20 mg/day

length of preoperative statin exposure: 7 days





stroke: +

renal failure: -



other key-outcomes: CRP

Notes

Risk of bias



bias)

Low risk “computer-generated randomization se-

quence”

Allocation concealment (selection bias) Low risk “sealed envelope”


bias)

All outcomes

Low risk “surgeons and investigators performing

post-operative assessments were unaware or

the randomization assignment”


All outcomes

Low risk “four patients were excluded...”



Other bias Unclear risk e.g. lacking study protocol

Sample size calculation High risk not reported


treat analysis




Ji 2009 (Continued)


Mannacio 2008



Participants inclusion criteria: CABG

total number: 200

Interventions statin type: rosuvastatin, n=100

dose: 20 mg/day


control-group: placebo, n= 100




stroke: -

renal failure: +



other key-outcomes: myocardial damage, hsCRP

Notes

Risk of bias



bias)

Low risk “computer-generated algorithm”



bias)

All outcomes

Low risk “Randomization was fully blinded, with-

out any account of clinical or demographic

features.”


All outcomes

Low risk no incomplete data


pected outcome data reported (except mor-

tality)


bias



Mannacio 2008 (Continued)


culation


treat analysis



Patti 2006



Participants inclusion criteria: on-pump cardiac surgery

total number: 200

Interventions statin type: atrovastatin, n=101

dose: 40 mg/day






stroke: +

renal failure: -



other key-outcomes: -

Notes

Risk of bias



bias)

Low risk “computer-generated randomization ... sta-

tistical consultant”

Allocation concealment (selection bias) Low risk “randomization assignment for each pa-

tient was kept in a sealed envelope”


bias)

All outcomes

Low risk “the assigned therapy was fully blinded;

surgeons and investigators performing

post-operative assessment were not aware

of the randomization assignment”



Patti 2006 (Continued)


All outcomes





bias


culation

analysis of intention-to-treat Low risk “all patients continued the assigned,

blinded treatment”



Song 2008



Participants inclusion criteria: elective, off-pump CABG

total number: 124

Interventions statin type: atrovastatin, n=62

dose: 20 mg/day






stroke: +

renal failure: -



other key-outcomes: hsCRP, NTproBNP

Notes

Risk of bias




Song 2008 (Continued)


bias)

Low risk “using a randomization table”



bias)

All outcomes

High risk “this study was not done as a double-blind,

placebo-controlled trial”


All outcomes




Other bias Unclear risk e.g. study protocol not available


culation


treat analysis



Spadaccio 2010




total number: 50


dose: 20 mg/day






stroke: +

renal failure: -



other key-outcomes: IL-6/-8, TNF-a, VEGF, GSCF, EPC-count



Spadaccio 2010 (Continued)

Notes

Risk of bias



bias)




bias)

All outcomes

Low risk “both patients and physicians were blinded

to the drug assignment”


All outcomes





bias


culation

analysis of intention-to-treat Low risk no side effects of drugs, i.e. ITT



Tamayo 2009




total number: 44


doses: 20 mg/day





Tamayo 2009 (Continued)


myocardial infarction: -


stroke: -

renal failure: -



other key-outcomes: SIRS, IL-6/-8, TNF-a

Notes

Risk of bias



bias)




bias)

All outcomes

Low risk “except the perfusionists, the clinical team

was blinded to the randomization”


All outcomes




Other bias Unclear risk e.g. study protocol not available


culation

analysis of intention-to-treat Low risk no patient died, all completed study un-

eventful





Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Ali 2005 not randomized controlled trial

Barbir 1994 only post-operative initiation of statins

Borger 2010 not randomized controlled trial

Brophy 2005 only post-operative initiation of statins

Brull 2001 not randomized controlled trial

Cannon 2004 no adequate control-group

Carrier 2009 retrospective study design

Chello 2003 not randomized controlled trial

Chello 2004 not randomized controlled trial

Cherkanova 2009 non relevant outcomes investigated

Christenson 2001a retrospective study design

Collard 2006 not randomized controlled trial

Dereli 2008 not randomized controlled trial

Dotani 2000 retrospective study design

Dotani 2003 non relevant outcomes investigated

Fedoruk 2008 retrospective study design

Huffmyer 2009 retrospective study design

Kasai 2009 retrospective study design

Kourliouros 2008 retrospective study design

Krivoy 2008 not randomized controlled trial

Kulik 2008 retrospective study design

Kumar 2006 no adequate control-group

Kurban 2009 not randomized controlled trial



(Continued)

Lertsburapa 2008 different co-intervention

Liakopoulos 2006 not randomized controlled trial

Mariscalco 2007 retrospective study design

Martinez-Comendador 2009 not randomized controlled trial

Miceli 2009 retrospective study design

Mohamed 2009 retrospective study design

Mukamal 2006 different co-intervention

Nakamura 2006 only post-operative initiation of statins

Ouattara 2009 not randomized controlled trial

Ozaydin 2007 not randomized controlled trial

Pan 2004 retrospective study design

Papathanasiou 2008 retrospective study design

Pascual 2006 not randomized controlled trial

Radaelli 2007 no adequate control-group

Sharma 2005 no adequate control-group

Subramaniam 2008 not randomized controlled trial

Tabata 2007 retrospective study design

Tabata 2008 retrospective study design

Thielmann 2007 retrospective study design

Virani 2008 retrospective study design

Zhang 2009 retrospective study design



Characteristics of studies awaiting assessment [ordered by study ID]

Antoniades 2010

Methods study design: randomized trial


Participants inclusion criteria: CABG

total number: 42


dose: 40 mg/day



Outcomes mortality:

myocardial infarction:


stroke:

renal failure:

length of stay on ICU:

length of stay in hospital:

other key-outcomes: O2-, NADPH-oxidase activity, Rac1, MDA

Notes desired outcomes not reported, but eventually recorded

DECISION: additional data provided after contacting by email, but outcome data of interest still pending even after

multiple email contacts. mails

Chello 2005

Methods study design: randomized trial

total study duration: May 2003 - September 2004


total number: 42


dose: 20 mg/day



“normal group”: volunteers, n=20




stroke:

renal failure:



other key-outcomes: endothelial function



Chello 2005 (Continued)

Notes unclear: nearly same data set (i.e. redundant?) as published in Chello 2006 (number of patients, intervention etc.),

but patient cohort slightly different!

DECISION: no answer after contacting author

Chello 2007




total number: 30

Interventions statin type: simvastatin, n= 15

dose: 40 mg/day


control-group: placebo

Outcomes mortality:



stroke:

renal failure:



other key-outcomes:IL-6/-8, TNF-a, neutrophil isolation/activation, apoptosis, caspases

Notes desired outcomes not reported, but eventually recorded; nearly same data set (i.e. redundant?) as published in Chello

2006 (number of patients, intervention etc.)


Coccia 2007




total number: 40


dose: 40 mg/day


control-group: placebo, n= 20

Outcomes mortality:



stroke:



Coccia 2007 (Continued)

renal failure:



other key-outcomes: membrane fluidity, erythrocyte anion permeability, lipid peroxidation, hmolysis indices

Notes desired outcomes not reported, but eventually recorded


Song 2007

Methods Study design: RCT

Total study duration: 05.2006-05.2007

Participants Inclusion Criteria: elective, off-pump CABG

Total number: 124

Interventions Statin type: Atorvastatin, n=62

Dose: 20 mg/day

Length of preoperative statin exposure: 3 days

Control-group: control, n=62

Outcomes Mortality: +

Myocardial infarction: +

Atrial fibrillation: +

Stroke: +

Renal failure: -

Length of stay on ICU: +

Length of stay in hospital: +

Other key-outcomes: hsCRP, NTproBNP

Notes

Characteristics of ongoing studies [ordered by study ID]

Bellomo 2008

Trial name or title The Effect of Atorvastatin on post-operative Renal Function After Cardiac Surgery

Methods Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Safety/Efficacy Study, Interven-

tion Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Asses-

sor), Primary Purpose: Treatment

Participants Inclusion Criteria:

- Cardiac surgical patients in whom the use of cardiopulmonary bypass was planned

- Written informed consent of patient

- Age > 18 years

- And having at least one ore more of the following risk factors for post-operative AKI:



Bellomo 2008 (Continued)

- Age =/> 70 years

- Preoperative plasma creatinine >120 µmol/L, New York Heart Association class III/IV or LVEF <35%

- Insulin dependent diabetes mellitus

- Valve surgery (with or without coronary artery bypass graft)

- Redo cardiac surgery

Interventions Drug: Atorvastatin

Drug: Placebo

Outcomes primary:

Change in serum creatinine from baseline to peak level within first two-seven post-operative days No

secondary:

Proportion of patients developing an increase in serum creatinine > 25% or >44µmicromol/L from baseline

to peak level within first two-seven post-operative days No

Proportion of patients developing any of the RIFLE criteria: R, I or F within first seven post-operative days

No

Proportion of patients developing any of the AKI stages: 1, 2 or 3 (using network definition) within first

seven post-operative days No

Change in NGAL from baseline to peak within first 24 post-operatively No

Requirement of renal replacement therapy within hospital stay No

Length of stay in Intensive care from admission to discharge from Intensive care No

Length of stay in Hospital from admission to discharge from hospital No

Hospital-Mortality during hospital stay No

Starting date March 2008

Contact information Rinaldo Bellomo, MD, FRACP; tel.: 61-3-9496-5992; [email protected]

Notes Status of study “unknown” (information current as May 4th, 2011); “No” in outcomes unclear

Billings 2009

Trial name or title Short-term Atorvastatin’s Effect on Acute Kidney Injury Following Cardiac Surgery

Methods Allocation: Randomized, Control: Placebo Control, Endpoint Classification: Efficacy Study, Intervention

Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor),

Primary Purpose: Prevention

Participants open heart surgery

Interventions Drug: atorvastatin

Drug: placebo

Outcomes primary:

acute kidney injury at randomization, at anesthesia induction, and post-operative days 1, 2, and 3, up to 6

months. No

delirium at randomization, daily post-operatively while in ICU, and up to 6 months No

secondary:



Billings 2009 (Continued)

dialysis until post-operative ICU discharge. No

urine markers of renal injury at randomization, anesthesia induction, 30 minutes into cardiopulm bypass

(CPB), after CPB, ICU admission, 6 hours postop, 12 hours postop, and POD 1, 2, 3. No

plasma markers of inflammation at randomization, anesthesia induction, 30 minutes into cardiopulm bypass

(CPB), after CPB, ICU admission, 6 hours postop, and POD 1, 2, 3. No

liver enzymes post-operative day 1 Yes

stroke until post-operative ICU discharge No

death until post-operative hospital discharge & at 6 months No

plasma and urine markers of oxidative stress (f2-Isoprostanes) at randomization, anesthesia induction, 30

minutes into cardiopulm bypass (CPB), after CPB, ICU admission, 6 hours postop, and POD 1, 2, 3. No

Starting date July 2009

Contact information Frederic T. Billings, IV, MD; tel.: +16159368487; [email protected]

Notes “No” and “Yes” in outcomes unclear

Kindo 2008

Trial name or title Effects of High Dose Atorvastatin in Patients With Surgical Aortic Stenosis

Methods Allocation: Randomized, Control: Active Control, Endpoint Classification: Efficacy Study, Intervention

Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Participants Inclusion Criteria:

- Age > or = 70 years and < 80 years

- Severe aortic valve stenosis

- Indication for aortic valve replacement by bioprothesis

- Ejection fraction > or = 50%

- Without treatment with statin- No renal failure

- Informed consent signed

Interventions Drug: Atorvastatin 80 mg

Outcomes primary:

Phase I: To study changes on inflammatory markers after aortic valve replacement. Phase II: To study changes

in left ventricular mass at the end of the study (12 months). 1 year No

secondary:

Phase I: To study changes on mitochondrial function, reactive oxygen species, and perioperative systolic and

diastolic functions. Phase II: To study changes on clinical status, systolic and diastolic functions during the

one-year follow-up. 1 year No

Starting date December 2008

Contact information Michel Kindo, MD; tel.: 33.3.69.55.08.11; [email protected]

Notes “No” in outomes unclear



D A T A A N D A N A L Y S E S

Comparison 1. Outcomes

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Mortality 1 200 Odds Ratio (M-H, Fixed, 95% CI) 0.98 [0.14, 7.10]

2 Myocardial infarction 5 741 Odds Ratio (M-H, Fixed, 95% CI) 0.52 [0.20, 1.30]

3 Atrial fibrillation 8 841 Odds Ratio (M-H, Fixed, 95% CI) 0.40 [0.29, 0.55]

4 Stroke 2 264 Odds Ratio (M-H, Fixed, 95% CI) 0.70 [0.14, 3.63]

5 Renal failure 4 367 Odds Ratio (M-H, Fixed, 95% CI) 0.41 [0.15, 1.12]

6 Length of stay on ICU 7 521 Mean Difference (IV, Fixed, 95% CI) -3.39 [-5.77, -1.01]

7 Length of stay in hospital 8 877 Mean Difference (IV, Random, 95% CI) -0.48 [-0.85, -0.11]

Comparison 2. Only studies with CABG procedures


studies

No. of








Comparison 3. Only studies with ON-PUMP CABG procedures


studies

No. of










Comparison 4. Only studies with ELECTIVE CABG procedures


studies

No. of








Comparison 5. Only studies with ATORVASTATIN


studies

No. of






5 Length of stay on ICU 4 354 Mean Difference (IV, Fixed, 95% CI) -2.69 [-5.46, 0.08]

6 Length of stay in hospital 5 554 Mean Difference (IV, Fixed, 95% CI) -0.35 [-0.59, -0.10]

Comparison 6. Only studies with >21d STATIN ADMINISTRATION


studies

No. of


1 Myocardial infarction 2 201 Odds Ratio (M-H, Random, 95% CI) 0.43 [0.02, 12.03]




5 Length of stay in hospital 5 337 Mean Difference (IV, Random, 95% CI) -0.34 [-0.98, 0.30]



Analysis 1.1. Comparison 1 Outcomes, Outcome 1 Mortality.

Review: Preoperative statin therapy for patients undergoing cardiac surgery

Comparison: 1 Outcomes

Outcome: 1 Mortality

Study or subgroup Statin Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Patti 2006 2/101 2/99 100.0 % 0.98 [ 0.14, 7.10 ]

Total (95% CI) 101 99 100.0 % 0.98 [ 0.14, 7.10 ]

Total events: 2 (Statin), 2 (Control)

Heterogeneity: not applicable

Test for overall effect: Z = 0.02 (P = 0.98)

Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours experimental Favours control

Analysis 1.2. Comparison 1 Outcomes, Outcome 2 Myocardial infarction.



Outcome: 2 Myocardial infarction



Christenson 1999 0/40 5/37 43.3 % 0.07 [ 0.00, 1.37 ]

Ji 2009 0/71 1/69 11.6 % 0.32 [ 0.01, 7.97 ]

Mannacio 2008 1/100 2/100 15.2 % 0.49 [ 0.04, 5.55 ]

Patti 2006 3/101 3/99 22.6 % 0.98 [ 0.19, 4.97 ]

Song 2008 2/62 1/62 7.4 % 2.03 [ 0.18, 23.02 ]

Total (95% CI) 374 367 100.0 % 0.52 [ 0.20, 1.30 ]


Heterogeneity: Chi2 = 3.62, df = 4 (P = 0.46); I2 =0.0%



0.01 0.1 1 10 100




Analysis 1.3. Comparison 1 Outcomes, Outcome 3 Atrial fibrillation.



Outcome: 3 Atrial fibrillation



Caorsi 2008 5/21 8/22 5.1 % 0.55 [ 0.14, 2.06 ]

Chello 2006 2/20 5/20 3.9 % 0.33 [ 0.06, 1.97 ]

Ji 2009 10/71 23/69 17.3 % 0.33 [ 0.14, 0.76 ]

Mannacio 2008 18/100 35/100 24.7 % 0.41 [ 0.21, 0.78 ]

Patti 2006 35/101 56/99 31.8 % 0.41 [ 0.23, 0.72 ]

Song 2008 8/62 17/62 12.8 % 0.39 [ 0.15, 0.99 ]

Spadaccio 2010 2/25 4/25 3.2 % 0.46 [ 0.08, 2.75 ]

Tamayo 2009 0/22 1/22 1.3 % 0.32 [ 0.01, 8.25 ]

Total (95% CI) 422 419 100.0 % 0.40 [ 0.29, 0.55 ]



Test for overall effect: Z = 5.53 (P < 0.00001)


0.01 0.1 1 10 100




Analysis 1.4. Comparison 1 Outcomes, Outcome 4 Stroke.



Outcome: 4 Stroke



Ji 2009 0/71 1/69 43.8 % 0.32 [ 0.01, 7.97 ]

Song 2008 2/62 2/62 56.2 % 1.00 [ 0.14, 7.33 ]

Total (95% CI) 133 131 100.0 % 0.70 [ 0.14, 3.63 ]





0.01 0.1 1 10 100


Analysis 1.5. Comparison 1 Outcomes, Outcome 5 Renal failure.



Outcome: 5 Renal failure



Chello 2006 1/20 1/20 7.6 % 1.00 [ 0.06, 17.18 ]

Christenson 1999 3/40 8/37 61.2 % 0.29 [ 0.07, 1.21 ]

Mannacio 2008 1/100 3/100 23.6 % 0.33 [ 0.03, 3.19 ]

Spadaccio 2010 1/25 1/25 7.6 % 1.00 [ 0.06, 16.93 ]

Total (95% CI) 185 182 100.0 % 0.41 [ 0.15, 1.12 ]





0.01 0.1 1 10 100




Analysis 1.6. Comparison 1 Outcomes, Outcome 6 Length of stay on ICU.



Outcome: 6 Length of stay on ICU

Study or subgroup Statin ControlMean

Difference WeightMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Berkan 2009 23 34.43 (9.08) 23 42.87 (9.92) 18.8 % -8.44 [ -13.94, -2.94 ]

Chello 2006 20 45.6 (14.4) 20 50.4 (9.6) 9.9 % -4.80 [ -12.38, 2.78 ]

Christenson 1999 40 50.4 (19.2) 37 48 (21.6) 6.8 % 2.40 [ -6.76, 11.56 ]

Ji 2009 71 48.4 (8.6) 69 50.1 (10.5) 55.9 % -1.70 [ -4.88, 1.48 ]

Song 2008 62 45 (47) 62 44 (28) 3.1 % 1.00 [ -12.62, 14.62 ]

Spadaccio 2010 25 40.8 (21.6) 25 52.8 (16.8) 4.9 % -12.00 [ -22.73, -1.27 ]

Tamayo 2009 22 60 (55.2) 22 57.6 (43.2) 0.7 % 2.40 [ -26.89, 31.69 ]

Total (95% CI) 263 258 100.0 % -3.39 [ -5.77, -1.01 ]

Heterogeneity: Chi2 = 9.02, df = 6 (P = 0.17); I2 =33%



-20 -10 0 10 20




Analysis 1.7. Comparison 1 Outcomes, Outcome 7 Length of stay in hospital.



Outcome: 7 Length of stay in hospital



Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Berkan 2009 23 8.57 (1.56) 23 10.48 (2.39) 6.9 % -1.91 [ -3.08, -0.74 ]

Chello 2006 20 7.2 (0.9) 20 6.9 (1) 14.4 % 0.30 [ -0.29, 0.89 ]

Christenson 1999 40 11.6 (3.2) 37 11.5 (2.2) 6.5 % 0.10 [ -1.12, 1.32 ]

Ji 2009 71 12.4 (2.1) 69 12.8 (2.2) 12.3 % -0.40 [ -1.11, 0.31 ]

Mannacio 2008 100 8.2 (1.2) 100 9.1 (1.4) 18.6 % -0.90 [ -1.26, -0.54 ]

Patti 2006 101 6.3 (1.2) 99 6.9 (1.4) 18.6 % -0.60 [ -0.96, -0.24 ]

Song 2008 62 6.9 (3.2) 62 7.2 (3.3) 7.1 % -0.30 [ -1.44, 0.84 ]

Spadaccio 2010 25 6.8 (1) 25 7.1 (0.9) 15.5 % -0.30 [ -0.83, 0.23 ]

Total (95% CI) 442 435 100.0 % -0.48 [ -0.85, -0.11 ]

Heterogeneity: Tau2 = 0.16; Chi2 = 19.19, df = 7 (P = 0.01); I2 =64%



-2 -1 0 1 2




Analysis 2.1. Comparison 2 Only studies with CABG procedures, Outcome 1 Myocardial infarction.


Comparison: 2 Only studies with CABG procedures




Christenson 1999 0/40 5/37 43.3 % 0.07 [ 0.00, 1.37 ]

Ji 2009 0/71 1/69 11.6 % 0.32 [ 0.01, 7.97 ]

Mannacio 2008 1/100 2/100 15.2 % 0.49 [ 0.04, 5.55 ]

Patti 2006 3/101 3/99 22.6 % 0.98 [ 0.19, 4.97 ]

Song 2008 2/62 1/62 7.4 % 2.03 [ 0.18, 23.02 ]

Total (95% CI) 374 367 100.0 % 0.52 [ 0.20, 1.30 ]





0.01 0.1 1 10 100




Analysis 2.2. Comparison 2 Only studies with CABG procedures, Outcome 2 Atrial fibrillation.






Caorsi 2008 5/21 8/22 5.1 % 0.55 [ 0.14, 2.06 ]

Chello 2006 2/20 5/20 3.9 % 0.33 [ 0.06, 1.97 ]

Ji 2009 10/71 23/69 17.3 % 0.33 [ 0.14, 0.76 ]

Mannacio 2008 18/100 35/100 24.7 % 0.41 [ 0.21, 0.78 ]

Patti 2006 35/101 56/99 31.8 % 0.41 [ 0.23, 0.72 ]

Song 2008 8/62 17/62 12.8 % 0.39 [ 0.15, 0.99 ]

Spadaccio 2010 2/25 4/25 3.2 % 0.46 [ 0.08, 2.75 ]

Tamayo 2009 0/22 1/22 1.3 % 0.32 [ 0.01, 8.25 ]

Total (95% CI) 422 419 100.0 % 0.40 [ 0.29, 0.55 ]





0.01 0.1 1 10 100




Analysis 2.3. Comparison 2 Only studies with CABG procedures, Outcome 3 Stroke.



Outcome: 3 Stroke



Ji 2009 0/71 1/69 43.8 % 0.32 [ 0.01, 7.97 ]

Song 2008 2/62 2/62 56.2 % 1.00 [ 0.14, 7.33 ]

Total (95% CI) 133 131 100.0 % 0.70 [ 0.14, 3.63 ]





0.01 0.1 1 10 100


Analysis 2.4. Comparison 2 Only studies with CABG procedures, Outcome 4 Renal failure.






Chello 2006 1/20 1/20 7.6 % 1.00 [ 0.06, 17.18 ]

Christenson 1999 3/40 8/37 61.2 % 0.29 [ 0.07, 1.21 ]

Mannacio 2008 1/100 3/100 23.6 % 0.33 [ 0.03, 3.19 ]

Spadaccio 2010 1/25 1/25 7.6 % 1.00 [ 0.06, 16.93 ]

Total (95% CI) 185 182 100.0 % 0.41 [ 0.15, 1.12 ]





0.01 0.1 1 10 100




Analysis 2.5. Comparison 2 Only studies with CABG procedures, Outcome 5 Length of stay on ICU.






Difference


Berkan 2009 23 34.43 (9.08) 23 42.87 (9.92) 18.8 % -8.44 [ -13.94, -2.94 ]

Chello 2006 20 45.6 (14.4) 20 50.4 (9.6) 9.9 % -4.80 [ -12.38, 2.78 ]

Christenson 1999 40 50.4 (19.2) 37 48 (21.6) 6.8 % 2.40 [ -6.76, 11.56 ]

Ji 2009 71 48.4 (8.6) 69 50.1 (10.5) 55.9 % -1.70 [ -4.88, 1.48 ]

Song 2008 62 45 (47) 62 44 (28) 3.1 % 1.00 [ -12.62, 14.62 ]

Spadaccio 2010 25 40.8 (21.6) 25 52.8 (16.8) 4.9 % -12.00 [ -22.73, -1.27 ]

Tamayo 2009 22 60 (55.2) 22 57.6 (43.2) 0.7 % 2.40 [ -26.89, 31.69 ]

Total (95% CI) 263 258 100.0 % -3.39 [ -5.77, -1.01 ]




-100 -50 0 50 100




Analysis 2.6. Comparison 2 Only studies with CABG procedures, Outcome 6 Length of stay in hospital.






Difference


Berkan 2009 23 8.57 (1.56) 23 10.48 (2.39) 6.9 % -1.91 [ -3.08, -0.74 ]

Chello 2006 20 7.2 (0.9) 20 6.9 (1) 14.4 % 0.30 [ -0.29, 0.89 ]

Christenson 1999 40 11.6 (3.2) 37 11.5 (2.2) 6.5 % 0.10 [ -1.12, 1.32 ]

Ji 2009 71 12.4 (2.1) 69 12.8 (2.2) 12.3 % -0.40 [ -1.11, 0.31 ]

Mannacio 2008 100 8.2 (1.2) 100 9.1 (1.4) 18.6 % -0.90 [ -1.26, -0.54 ]

Patti 2006 101 6.3 (1.2) 99 6.9 (1.4) 18.6 % -0.60 [ -0.96, -0.24 ]

Song 2008 62 6.9 (3.2) 62 7.2 (3.3) 7.1 % -0.30 [ -1.44, 0.84 ]

Spadaccio 2010 25 6.8 (1) 25 7.1 (0.9) 15.5 % -0.30 [ -0.83, 0.23 ]

Total (95% CI) 442 435 100.0 % -0.48 [ -0.85, -0.11 ]




-2 -1 0 1 2




Analysis 3.1. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 1 Myocardial

infarction.


Comparison: 3 Only studies with ON-PUMP CABG procedures




Christenson 1999 0/40 5/37 46.7 % 0.07 [ 0.00, 1.37 ]

Ji 2009 0/71 1/69 12.5 % 0.32 [ 0.01, 7.97 ]

Mannacio 2008 1/100 2/100 16.4 % 0.49 [ 0.04, 5.55 ]

Patti 2006 3/101 3/99 24.4 % 0.98 [ 0.19, 4.97 ]

Total (95% CI) 312 305 100.0 % 0.39 [ 0.14, 1.12 ]





0.01 0.1 1 10 100




Analysis 3.2. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 2 Atrial fibrillation.






Caorsi 2008 5/21 8/22 5.9 % 0.55 [ 0.14, 2.06 ]

Chello 2006 2/20 5/20 4.4 % 0.33 [ 0.06, 1.97 ]

Ji 2009 10/71 23/69 19.8 % 0.33 [ 0.14, 0.76 ]

Mannacio 2008 18/100 35/100 28.3 % 0.41 [ 0.21, 0.78 ]

Patti 2006 35/101 56/99 36.5 % 0.41 [ 0.23, 0.72 ]

Spadaccio 2010 2/25 4/25 3.6 % 0.46 [ 0.08, 2.75 ]

Tamayo 2009 0/22 1/22 1.4 % 0.32 [ 0.01, 8.25 ]

Total (95% CI) 360 357 100.0 % 0.40 [ 0.28, 0.56 ]





0.01 0.1 1 10 100


Analysis 3.3. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 3 Stroke.



Outcome: 3 Stroke



Ji 2009 0/71 1/69 100.0 % 0.32 [ 0.01, 7.97 ]

Total (95% CI) 71 69 100.0 % 0.32 [ 0.01, 7.97 ]


Heterogeneity: not applicable



0.01 0.1 1 10 100




Analysis 3.4. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 4 Renal failure.






Chello 2006 1/20 1/20 7.6 % 1.00 [ 0.06, 17.18 ]

Christenson 1999 3/40 8/37 61.2 % 0.29 [ 0.07, 1.21 ]

Mannacio 2008 1/100 3/100 23.6 % 0.33 [ 0.03, 3.19 ]

Spadaccio 2010 1/25 1/25 7.6 % 1.00 [ 0.06, 16.93 ]

Total (95% CI) 185 182 100.0 % 0.41 [ 0.15, 1.12 ]





0.01 0.1 1 10 100




Analysis 3.5. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 5 Length of stay on

ICU.






Difference


Berkan 2009 23 34.43 (9.08) 23 42.87 (9.92) 19.4 % -8.44 [ -13.94, -2.94 ]

Chello 2006 20 45.6 (14.4) 20 50.4 (9.6) 10.2 % -4.80 [ -12.38, 2.78 ]

Christenson 1999 40 50.4 (19.2) 37 48 (21.6) 7.0 % 2.40 [ -6.76, 11.56 ]

Ji 2009 71 48.4 (8.6) 69 50.1 (10.5) 57.7 % -1.70 [ -4.88, 1.48 ]

Spadaccio 2010 25 40.8 (21.6) 25 52.8 (16.8) 5.1 % -12.00 [ -22.73, -1.27 ]

Tamayo 2009 22 60 (55.2) 22 57.6 (43.2) 0.7 % 2.40 [ -26.89, 31.69 ]

Total (95% CI) 201 196 100.0 % -3.53 [ -5.95, -1.11 ]




-100 -50 0 50 100




Analysis 3.6. Comparison 3 Only studies with ON-PUMP CABG procedures, Outcome 6 Length of stay in

hospital.






Difference


Berkan 2009 23 8.57 (1.56) 23 10.48 (2.39) 7.8 % -1.91 [ -3.08, -0.74 ]

Chello 2006 20 7.2 (0.9) 20 6.9 (1) 15.5 % 0.30 [ -0.29, 0.89 ]

Christenson 1999 40 11.6 (3.2) 37 11.5 (2.2) 7.3 % 0.10 [ -1.12, 1.32 ]

Ji 2009 71 12.4 (2.1) 69 12.8 (2.2) 13.4 % -0.40 [ -1.11, 0.31 ]

Mannacio 2008 100 8.2 (1.2) 100 9.1 (1.4) 19.7 % -0.90 [ -1.26, -0.54 ]

Patti 2006 101 6.3 (1.2) 99 6.9 (1.4) 19.7 % -0.60 [ -0.96, -0.24 ]

Spadaccio 2010 25 6.8 (1) 25 7.1 (0.9) 16.6 % -0.30 [ -0.83, 0.23 ]

Total (95% CI) 380 373 100.0 % -0.49 [ -0.89, -0.10 ]




-2 -1 0 1 2




Analysis 4.1. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 1 Myocardial

infarction.


Comparison: 4 Only studies with ELECTIVE CABG procedures




Ji 2009 0/71 1/69 20.4 % 0.32 [ 0.01, 7.97 ]

Mannacio 2008 1/100 2/100 26.8 % 0.49 [ 0.04, 5.55 ]

Patti 2006 3/101 3/99 39.7 % 0.98 [ 0.19, 4.97 ]

Song 2008 2/62 1/62 13.1 % 2.03 [ 0.18, 23.02 ]

Total (95% CI) 334 330 100.0 % 0.85 [ 0.29, 2.47 ]





0.01 0.1 1 10 100




Analysis 4.2. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 2 Atrial fibrillation.






Caorsi 2008 5/21 8/22 5.1 % 0.55 [ 0.14, 2.06 ]

Chello 2006 2/20 5/20 3.9 % 0.33 [ 0.06, 1.97 ]

Ji 2009 10/71 23/69 17.3 % 0.33 [ 0.14, 0.76 ]

Mannacio 2008 18/100 35/100 24.7 % 0.41 [ 0.21, 0.78 ]

Patti 2006 35/101 56/99 31.8 % 0.41 [ 0.23, 0.72 ]

Song 2008 8/62 17/62 12.8 % 0.39 [ 0.15, 0.99 ]

Spadaccio 2010 2/25 4/25 3.2 % 0.46 [ 0.08, 2.75 ]

Tamayo 2009 0/22 1/22 1.3 % 0.32 [ 0.01, 8.25 ]

Total (95% CI) 422 419 100.0 % 0.40 [ 0.29, 0.55 ]





0.01 0.1 1 10 100




Analysis 4.3. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 3 Stroke.



Outcome: 3 Stroke



Ji 2009 0/71 1/69 43.8 % 0.32 [ 0.01, 7.97 ]

Song 2008 2/62 2/62 56.2 % 1.00 [ 0.14, 7.33 ]

Total (95% CI) 133 131 100.0 % 0.70 [ 0.14, 3.63 ]





0.01 0.1 1 10 100


Analysis 4.4. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 4 Renal failure.






Chello 2006 1/20 1/20 19.5 % 1.00 [ 0.06, 17.18 ]

Mannacio 2008 1/100 3/100 60.9 % 0.33 [ 0.03, 3.19 ]

Spadaccio 2010 1/25 1/25 19.7 % 1.00 [ 0.06, 16.93 ]

Total (95% CI) 145 145 100.0 % 0.59 [ 0.14, 2.53 ]





0.01 0.1 1 10 100




Analysis 4.5. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 5 Length of stay on

ICU.






Difference


Berkan 2009 23 34.43 (9.08) 23 42.87 (9.92) 20.1 % -8.44 [ -13.94, -2.94 ]

Chello 2006 20 45.6 (14.4) 20 50.4 (9.6) 10.6 % -4.80 [ -12.38, 2.78 ]

Ji 2009 71 48.4 (8.6) 69 50.1 (10.5) 60.0 % -1.70 [ -4.88, 1.48 ]

Song 2008 62 45 (47) 62 44 (28) 3.3 % 1.00 [ -12.62, 14.62 ]

Spadaccio 2010 25 40.8 (21.6) 25 52.8 (16.8) 5.3 % -12.00 [ -22.73, -1.27 ]

Tamayo 2009 22 60 (55.2) 22 57.6 (43.2) 0.7 % 2.40 [ -26.89, 31.69 ]

Total (95% CI) 223 221 100.0 % -3.81 [ -6.28, -1.35 ]




-100 -50 0 50 100




Analysis 4.6. Comparison 4 Only studies with ELECTIVE CABG procedures, Outcome 6 Length of stay in

hospital.






Difference


Berkan 2009 23 8.57 (1.56) 23 10.48 (2.39) 7.5 % -1.91 [ -3.08, -0.74 ]

Chello 2006 20 7.2 (0.9) 20 6.9 (1) 15.4 % 0.30 [ -0.29, 0.89 ]

Ji 2009 71 12.4 (2.1) 69 12.8 (2.2) 13.2 % -0.40 [ -1.11, 0.31 ]

Mannacio 2008 100 8.2 (1.2) 100 9.1 (1.4) 19.8 % -0.90 [ -1.26, -0.54 ]

Patti 2006 101 6.3 (1.2) 99 6.9 (1.4) 19.8 % -0.60 [ -0.96, -0.24 ]

Song 2008 62 6.9 (3.2) 62 7.2 (3.3) 7.7 % -0.30 [ -1.44, 0.84 ]

Spadaccio 2010 25 6.8 (1) 25 7.1 (0.9) 16.6 % -0.30 [ -0.83, 0.23 ]

Total (95% CI) 402 398 100.0 % -0.52 [ -0.91, -0.13 ]




-2 -1 0 1 2




Analysis 5.1. Comparison 5 Only studies with ATORVASTATIN, Outcome 1 Myocardial infarction.


Comparison: 5 Only studies with ATORVASTATIN




Ji 2009 0/71 1/69 27.9 % 0.32 [ 0.01, 7.97 ]

Patti 2006 3/101 3/99 54.3 % 0.98 [ 0.19, 4.97 ]

Song 2008 2/62 1/62 17.9 % 2.03 [ 0.18, 23.02 ]

Total (95% CI) 234 230 100.0 % 0.98 [ 0.30, 3.25 ]





0.01 0.1 1 10 100


Analysis 5.2. Comparison 5 Only studies with ATORVASTATIN, Outcome 2 Atrial fibrillation.






Chello 2006 2/20 5/20 5.6 % 0.33 [ 0.06, 1.97 ]

Ji 2009 10/71 23/69 25.1 % 0.33 [ 0.14, 0.76 ]

Patti 2006 35/101 56/99 46.2 % 0.41 [ 0.23, 0.72 ]

Song 2008 8/62 17/62 18.5 % 0.39 [ 0.15, 0.99 ]

Spadaccio 2010 2/25 4/25 4.6 % 0.46 [ 0.08, 2.75 ]

Total (95% CI) 279 275 100.0 % 0.38 [ 0.26, 0.57 ]





0.01 0.1 1 10 100




Analysis 5.3. Comparison 5 Only studies with ATORVASTATIN, Outcome 3 Stroke.



Outcome: 3 Stroke



Ji 2009 0/71 1/69 43.8 % 0.32 [ 0.01, 7.97 ]

Song 2008 2/62 2/62 56.2 % 1.00 [ 0.14, 7.33 ]

Total (95% CI) 133 131 100.0 % 0.70 [ 0.14, 3.63 ]





0.01 0.1 1 10 100


Analysis 5.4. Comparison 5 Only studies with ATORVASTATIN, Outcome 4 Renal failure.






Chello 2006 1/20 1/20 49.7 % 1.00 [ 0.06, 17.18 ]

Spadaccio 2010 1/25 1/25 50.3 % 1.00 [ 0.06, 16.93 ]

Total (95% CI) 45 45 100.0 % 1.00 [ 0.13, 7.43 ]





0.01 0.1 1 10 100




Analysis 5.5. Comparison 5 Only studies with ATORVASTATIN, Outcome 5 Length of stay on ICU.






Difference


Chello 2006 20 45.6 (14.4) 20 50.4 (9.6) 13.4 % -4.80 [ -12.38, 2.78 ]

Ji 2009 71 48.4 (8.6) 69 50.1 (10.5) 75.8 % -1.70 [ -4.88, 1.48 ]

Song 2008 62 45 (47) 62 44 (28) 4.1 % 1.00 [ -12.62, 14.62 ]

Spadaccio 2010 25 40.8 (21.6) 25 52.8 (16.8) 6.7 % -12.00 [ -22.73, -1.27 ]

Total (95% CI) 178 176 100.0 % -2.69 [ -5.46, 0.08 ]




-100 -50 0 50 100




Analysis 5.6. Comparison 5 Only studies with ATORVASTATIN, Outcome 6 Length of stay in hospital.






Difference


Patti 2006 101 6.3 (1.2) 99 6.9 (1.4) 45.4 % -0.60 [ -0.96, -0.24 ]

Ji 2009 71 12.4 (2.1) 69 12.8 (2.2) 11.7 % -0.40 [ -1.11, 0.31 ]

Spadaccio 2010 25 6.8 (1) 25 7.1 (0.9) 21.3 % -0.30 [ -0.83, 0.23 ]

Song 2008 62 6.9 (3.2) 62 7.2 (3.3) 4.5 % -0.30 [ -1.44, 0.84 ]

Chello 2006 20 7.2 (0.9) 20 6.9 (1) 17.1 % 0.30 [ -0.29, 0.89 ]

Total (95% CI) 279 275 100.0 % -0.35 [ -0.59, -0.10 ]




-2 -1 0 1 2


Analysis 6.1. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 1 Myocardial

infarction.


Comparison: 6 Only studies with >21d STATIN ADMINISTRATION



n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Christenson 1999 0/40 5/37 47.0 % 0.07 [ 0.00, 1.37 ]

Song 2008 2/62 1/62 53.0 % 2.03 [ 0.18, 23.02 ]

Total (95% CI) 102 99 100.0 % 0.43 [ 0.02, 12.03 ]





0.01 0.1 1 10 100




Analysis 6.2. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 2 Atrial

fibrillation.






Chello 2006 2/20 5/20 18.4 % 0.33 [ 0.06, 1.97 ]

Song 2008 8/62 17/62 60.5 % 0.39 [ 0.15, 0.99 ]

Spadaccio 2010 2/25 4/25 15.0 % 0.46 [ 0.08, 2.75 ]

Tamayo 2009 0/22 1/22 6.0 % 0.32 [ 0.01, 8.25 ]

Total (95% CI) 129 129 100.0 % 0.39 [ 0.19, 0.80 ]





0.01 0.1 1 10 100




Analysis 6.3. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 3 Renal failure.






Chello 2006 1/20 1/20 9.9 % 1.00 [ 0.06, 17.18 ]

Christenson 1999 3/40 8/37 80.1 % 0.29 [ 0.07, 1.21 ]

Spadaccio 2010 1/25 1/25 10.0 % 1.00 [ 0.06, 16.93 ]

Total (95% CI) 85 82 100.0 % 0.43 [ 0.14, 1.34 ]





0.01 0.1 1 10 100




Analysis 6.4. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 4 Length of stay

on ICU.






Difference


Berkan 2009 23 34.43 (9.08) 23 42.87 (9.92) 42.6 % -8.44 [ -13.94, -2.94 ]

Chello 2006 20 45.6 (14.4) 20 50.4 (9.6) 22.4 % -4.80 [ -12.38, 2.78 ]

Christenson 1999 40 50.4 (19.2) 37 48 (21.6) 15.4 % 2.40 [ -6.76, 11.56 ]

Song 2008 62 45 (47) 62 44 (28) 6.9 % 1.00 [ -12.62, 14.62 ]

Spadaccio 2010 25 40.8 (21.6) 25 52.8 (16.8) 11.2 % -12.00 [ -22.73, -1.27 ]

Tamayo 2009 22 60 (55.2) 22 57.6 (43.2) 1.5 % 2.40 [ -26.89, 31.69 ]

Total (95% CI) 192 189 100.0 % -5.54 [ -9.13, -1.95 ]




-100 -50 0 50 100




Analysis 6.5. Comparison 6 Only studies with >21d STATIN ADMINISTRATION, Outcome 5 Length of stay

in hospital.






Difference


Berkan 2009 23 8.57 (1.56) 23 10.48 (2.39) 15.8 % -1.91 [ -3.08, -0.74 ]

Chello 2006 20 7.2 (0.9) 20 6.9 (1) 25.9 % 0.30 [ -0.29, 0.89 ]

Christenson 1999 40 11.6 (3.2) 37 11.5 (2.2) 15.1 % 0.10 [ -1.12, 1.32 ]

Song 2008 62 6.9 (3.2) 62 7.2 (3.3) 16.1 % -0.30 [ -1.44, 0.84 ]

Spadaccio 2010 25 6.8 (1) 25 7.1 (0.9) 27.1 % -0.30 [ -0.83, 0.23 ]

Total (95% CI) 170 167 100.0 % -0.34 [ -0.98, 0.30 ]




-2 -1 0 1 2


A P P E N D I C E S

Appendix 1. Search strategies

CENTRAL

#1 MeSH descriptor Cardiac Surgical Procedures explode all trees

#2 MeSH descriptor Cardiopulmonary Bypass, this term only

#3 MeSH descriptor Coronary Artery Bypass explode all trees

#4 heart near bypass*

#5 heart near surgery

#6 cardiac near surgery

#7 CABG

#8 coronary near surgery

#9 coronary near bypass*

#10 coronary near surgical

#11 cardiac near surgical

#12 valv* near surgery

#13 valv* near surgical

#14 valv* near replac*



#15 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14)

#16 MeSH descriptor Hydroxymethylglutaryl-CoA Reductase Inhibitors explode all trees

#17 hydroxymethylglutaryl*

#18 HMG-CoA*

#19 statin*

#20 atorvastatin or lipitor

#21 cerivastatin or baycol or zenas

#22 dalvastatin or RG 12561

#23 fluvastatin or cranoc or lescol or locol or fractal or fluindostatin

#24 lovastatin or mevinacor or mevacor or mevinolin or monacolin or medostatin

#25 pitavastatin or livalo or pitava

#26 pravastatin or mevalotin or pravasin or pravachol

#27 rosuvastatin or crestor

#28 simvastatin or gerosim or zocor or lipex

#29 MeSH descriptor Lovastatin, this term only

#30 MeSH descriptor Simvastatin, this term only

#31 MeSH descriptor Pravastatin, this term only

#32 (#16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30

OR #31)

#33 (#15 AND #32)

MEDLINE OVID

1. Cardiopulmonary Bypass/

2. (heart adj4 bypass*).tw.

3. (heart adj4 (surgery or surgical)).tw.

4. (cardiac adj4 (surgery or surgical)).tw.

5. exp Coronary Artery Bypass/

6. CABG.tw.

7. (coronary adj4 (surgery or surgical)).tw.

8. (coronary adj4 bypass*).tw.

9. exp Cardiac Surgical Procedures/

10. (valv* adj4 replac*).tw.

11. (valv* adj4 (surgery or surgical)).tw.

12. or/1-11

13. exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/

14. hydroxymethylglutaryl*.tw.

15. HMG-CoA*.tw.

16. (atorvastatin or lipitor).tw.

17. (cerivastatin or baycol or zenas).tw.

18. (dalvastatin or RG 12561).tw.

19. (fluvastatin or cranoc or lescol or locol or fractal or fluindostatin).tw.

20. Lovastatin/

21. (lovastatin or mevinacor or mevacor or mevinolin or monacolin or medostatin).tw.

22. (pitavastatin or livalo or pitava).tw.

23. Pravastatin/

24. (pravastatin or mevalotin or pravasin or pravachol).tw.

25. (rosuvastatin or crestor).tw.

26. Simvastatin/

27. (simvastatin or gerosim or zocor or lipex).tw.

28. or/13-24

29. randomized controlled trial.pt.

30. controlled clinical trial.pt.



31. randomized.ab.

32. placebo.ab.

33. drug therapy.fs.

34. randomly.ab.

35. trial.ab.

36. groups.ab.

37. 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36

38. exp animals/ not humans.sh.

39. 37 not 38

40. 12 and 28 and 39

EMBASE OVID

1. exp heart surgery/

2. (cardiopulmonary adj4 bypass$).tw.

3. (heart adj4 (surgery or surgical)).tw.

4. (cardiac adj4 (surgery or surgical)).tw.

5. (coronary adj4 bypass$).tw.

6. (heart adj4 bypass$).tw.

7. (coronary adj4 (surgery or surgical)).tw.

8. (valv* adj4 (surgery or surgical or replac*)).tw.

9. CABG.tw.

10. or/1-9

11. exp hydroxymethylglutaryl coenzyme A reductase Inhibitor/

12. hydroxymethylglutaryl$.tw.

13. HMG-CoA$.tw.

14. statin$.tw.

15. (atorvastatin or lipitor).tw.

16. (cerivastatin or baycol or zenas).tw.

17. (dalvastatin or RG 12561).tw.

18. (fluvastatin or cranoc or lescol or locol or fractal or fluindostatin).tw.

19. (lovastatin or mevinacor or mevacor or mevinolin or monacolin or medostatin).tw.

20. (pitavastatin or livalo or pitava).tw.

21. (pravastatin or mevalotin or pravasin or pravachol).tw.

22. (rosuvastatin or crestor).tw.

23. (simvastatin or gerosim or zocor or lipex).tw.

24. or/11-23

25. random$.tw.

26. factorial$.tw.

27. crossover$.tw.

28. cross-over$.tw.

29. placebo$.tw.

30. (doubl$ adj blind$).tw.

31. (singl$ adj blind$).tw.

32. assign$.tw.

33. allocat$.tw.

34. volunteer$.tw.

35. crossover procedure/

36. double blind procedure/

37. randomized controlled trial/

38. single blind procedure/

39. or/25-38

40. (animal/ or nonhuman/) not human/



41. 39 not 40

42. 10 and 24 and 41

H I S T O R Y

Protocol first published: Issue 4, 2010

Review first published: Issue 4, 2012

C O N T R I B U T I O N S O F A U T H O R S

Oliver J. Liakopoulos - primary author:

- Guarantor of the review,

- Development and organisation of the review team

- Conceive, design and coordinate the protocol and review

- Data collection for the review:

- Design and undertake search strategies

- Organize retrieval of papers

- Screen papers against eligibility criteria

- Appraise quality of papers

- Data analysis and interpretation

- Writing the review and protocol

- Updating the review

Elmar W. Kuhn - second reviewer

- Design the protocol and review

- Data collection for the review:

- Design and undertake search strategies

- Retrieve papers



- Extract data from papers

- Write to authors of papers for additional information

- Obtain and screen data from unpublished studies

- Data management, data entry into RevMan






Ingo Slottosch - third author



- Extract data from papers

- Write to authors of papers for additional information

- Obtain and screen data from unpublished studies


Gernot Wassmer (statistician) - fourth author


- Extract data, analyze and interpret results

- Provide general statistical recommendations for the review

Thorsten Wahlers - fifth author




D E C L A R A T I O N S O F I N T E R E S T

None.

S O U R C E S O F S U P P O R T

Internal sources

• No sources of support., Not specified.

External sources

• No sources of support supplied



preoperative statin therapy for patients undergoing ...statins (hmg-coa reductase inhibitors) have...

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