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Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing cardiac surgery: a meta-analysis of over 30 000 patients

Oliver J. Liakopoulos, Yeong-Hoon Choi, Peter L. Haldenwang, Justus Strauch, Thorsten Wittwer, Hilmar Dörge, Christof Stamm, Gernot Wassmer, Thorsten Wahlers
DOI: http://dx.doi.org/10.1093/eurheartj/ehn198 First published online: 27 May 2008

Abstract

Aims To determine the strength of evidence for preoperative statin use for prevention of adverse postoperative outcomes in patients undergoing cardiac surgery.

Methods and results After literature search in major databases, 19 studies were identified [three RCT (randomized prospective clinical trials), 16 observational] that reported outcomes of 31 725 cardiac surgery patients with (n = 17 201; 54%) or without (n = 14 524; 46%) preoperative statin therapy. Outcomes that were analysed included early all-cause mortality (30-day mortality), myocardial infarction (MI), atrial fibrillation (AF), stroke and renal failure. Odds ratio (OR) with 95% confidence intervals (95%CI) were reported using fixed or random effect models and publication bias was assessed. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95%CI: 0.49–0.67). A significant reduction (P < 0.01) in statin pretreated patients was also observed for AF (24.9 vs. 29.3%; OR 0.67, 95%CI: 0.51–0.88), stroke (2.1 vs. 2.9%, OR 0.74, 95%CI: 0.60–0.91), but not for MI (OR 1.11; 95%CI: 0.93–1.33) or renal failure (OR 0.78, 95%CI: 0.46–1.31). Funnel plot and Egger’s regression analysis (P = 0.60) excluded relevant publication bias.

Conclusion Our meta-analysis provides evidence that preoperative statin therapy exerts substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients, but underscores the need for RCT trials.

Keywords
  • Meta-analysis
  • Hydroxymethylglutaryl-coenzyme A reductase inhibitors
  • Statins
  • Cardiac surgery
  • Clinical outcomes

Introduction

Long-term lipid-lowering therapy with inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins) prevents progression of atherosclerotic coronary artery and vein graft disease, reduces the need for repeat revascularization and ultimately decreases adverse cardiovascular events and mortality in patients after coronary artery bypass grafting (CABG).1,2 Beyond their lipid-lowering actions, statins are known to exert multiple pleiotropic effects including improved endothelial function, plaque stabilization, decrease of inflammatory markers and attenuation of myocardial ischaemia-reperfusion injury that can offer direct organ protection and contribute to improved clinical outcome in the early postoperative course.35 Accumulating evidence from recent trials also suggests that statin use in patients undergoing non-cardiac surgery improves the early postoperative outcome by reducing adverse cardiovascular events and all-cause mortality.6,7

However in patients undergoing cardiac surgery results are conflicting with several studies reporting a decrease in short-term mortality and major cardiovascular events including myocardial infarction (MI), atrial fibrillation (AF), stroke, and renal failure in patients receiving preoperative statins,811 while others have failed to show a beneficial effect of statins on these endpoints.1216 These discrepancies arise primarily from the predominantly retrospective design of these studies, with inability to control for confounding factors such as preoperative patient risk factors and medications.17 Attempts to elucidate the potential benefits of a preoperative statin therapy in cardiac surgery were made by previous reviews that unfortunately lacked from sufficient power and suffered from potential publication bias, making interpretation of the presented data difficult.18,19 Thus, statin utilization in patients with CAD (coronary artery disease) admitted for cardiac surgery remains suboptimal (∼40%),20 despite existing guidelines of the ACC/AHA, NCEP, and ATPIII to aggressively lower lipids in this high-risk patient population,21 and underscores the need for providing further robust evidence in order to change current clinical practice.

In view of the limited clarity of available data, we conducted a systematic review and meta-analysis to assess the strength of evidence supporting the use of statins before cardiac surgery with the primary objective to determine if statins reduce early, all-cause mortality and decrease the incidence of major adverse postoperative events. Additionally, we desired to quantify the magnitude of treatment effects. The secondary objective was to identify confounding factors that may limit the estimated treatment effects on the measured endpoints.

Methods

Study inclusion and exclusion criteria

This systematic review was performed according to the guidelines for Quality of Reporting of Meta-analysis (QUORUM, MOOSE).22,23 Randomized prospective clinical trials (RCT) and observational studies published between 1966 and February 2008 that reported the effects of preoperative statin therapy on postoperative outcomes in adult patients undergoing cardiac surgery were identified and analysed using following a priori defined inclusion criteria: (i) use of any commercially available statin before cardiac surgery for any given duration and dose, (ii) studies comparing patients with or without preoperative statin therapy, and (iii) reported data on the incidence of desired postoperative clinical endpoints including early all-cause mortality, MI, AF, stroke, and renal failure. Early mortality was defined as death from any cause occurring during hospitalization or within 30 days after surgery. Definitions for the occurrence of perioperative MI included: (i) relevant elevation of perioperative markers of cardiac damage (CK-MB level three times greater than upper normal level, CK-MB fraction >10%, relevant troponin elevation), (ii) new ECG changes (Q-waves, persistent T-wave or ST-segment changes, loss of R-wave), (iii) clinical signs of myocardial ischaemia, and (iv) MI diagnosed at autopsy. Perioperative MI was considered to have occurred when at least one of the four aforementioned criteria was met. AF was defined as occurrence of any type of postoperative AF disregarding atrial flutter or supraventricular tachycardia. We accepted the authors’ definition for stroke and renal failure. Stroke was diagnosed if there was clinical or radiological evidence for neurological deficit or defect. Renal failure was recorded if a significant elevation of postoperative serum creatinine levels occurred (creatinine >2.0 mg/dL) or when patients required dialysis after surgery.

Studies not including a control group drawn from the same population, animal studies, in-vitro studies, or trials that exclusively reported other clinical outcomes were excluded. Case reports, editorials, comments, letters, review articles, guidelines or secondary prevention trials were also excluded from the analysis.

Search strategy

Two authors (O.J.L. and Y-H.C.) independently performed an electronic literature search in MEDLINE, EMBASE and The Cochrane Library (Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews and Effects, The Cochrane Central Register of Controlled Trials) using a predefined keywords list (Supplementary data S1). All human studies published in full-text or abstract forms were eligible for inclusion without applying any language restrictions. In addition, abstracts and oral presentations from the past 3 years scientific meetings (2005–2007) of the Society of Thoracic Surgeons (STS), European Association of Cardiothoracic Surgery (EACTS), American Association of Thoracic Surgery (AATS), European Society of Cardiology (ESC), American Heart Association (AHA), Society of Cardiovascular Anesthesiology (SCA) and American Society of Anesthesiologists (ASA) were screened. All titles and abstracts from the electronic search were uploaded into a reference management software database. After initial abstract review all potentially relevant studies were identified and the full-text publication retrieved for detailed evaluation. When more than one publication from the same patient cohort existed, then the study with the most complete data set was included in the systematic review. Furthermore, reference lists of potentially relevant reports and reviews were screened to identify other eligible studies.

Data extraction and quality assessment

All data with regard to authorship, year of publication, type of publication (abstract, oral presentation, full-text report), study design (RCT, observational study), study population (sample size, age, type of cardiac operation), length of preoperative statin exposure, applied statin regimen, length of follow-up and clinical endpoints were extracted. Methodological quality of the included studies was assessed by two independent investigators using the Jadad Score24 for RCT, and the Downs and Black Checklist25 for both RCT and observational trials, respectively. The Jadad Score is a validated five-point scale (0–2: poor quality, 3–4: good quality, 5: excellent quality) that examines the methods of randomization, double-blinding, and the reporting of dropouts. The Downs and Black tool comprises six sections that assess reporting (total score: 11), external validity (total score: 3), internal validity bias (total score: 7), internal validity confounding (total score: 6), and power (total score: 2). A maximum score of 29 indicates the highest methodological quality and a score of zero represents the poorest methodological quality. The consensus process to resolve disagreements required investigators to discuss the decisions with mandatory recognition of errors from one of the reviewers.

Statistical analysis

Statistical analyses were performed using RevMan (Version 4.2.1; The Nordic Cochrane Centre, Købehavn, Denmark) and the MIX software package (Version 1.61).26 For each individual study, either raw incidence data for clinical endpoints or the estimated effects expressed as the odds ratio (OR) and its 95% confidence interval (95%CI) were used and summarized by Forest plots. Q-statistics (P < 0.10) or I2-statistics (I2 > 50%) was performed to test for heterogeneity between included studies.27 A standard fixed effects model (Mantel–Haenszel method) was used in the absence of heterogeneity among studies. In the presence of heterogeneity the DerSimonian and Laird random effects model was used.28 Pooled treatment effect estimate was calculated as a weighted average of the treatment effects so that an OR < 1 favoured statin treatment over control. For continuous variables the weighted mean difference (WMD) was calculated. In studies reporting the median and quartiles, the median was assumed to most accurately represent the tendency and was treated as the mean. When needed, missing information or clarification about the data presented was retrieved by contacting the primary authors of the study.

A funnel plot was constructed to assess the presence of publication bias and examine differences between the effects in large and small studies. The treatment effects, given as the OR on a logarithmic scale, were plotted against a measure of precision expressed as the inverse standard error. In the absence of publication bias, the funnel plot would resemble an inverted, symmetrical funnel with less precise studies scattered at the bottom of the plot. Additionally, publication bias was assessed by applying the Egger’s weighted regression statistic with a P-value <0.05 indicating significant publication bias among included studies. Correction for publication bias was performed using the Trim-and-Fill method described by Duval and Tweedie29 that approximates the number of unpublished studies needed to achieve symmetry of the funnel plot, thereby recalculating an adjusted OR.

Results

Selection and characteristics of included studies

Search of the literature retrieved 1197 studies from the screened databases of which 1164 (97.3%) were excluded after initial review for reasons explained in Figure 1. Of the remaining 33 studies, 14 studies were excluded after detailed, full-text evaluation either due to insufficient reporting of desired clinical endpoints (n = 11)5,3039 or due to inclusion of the same patient population in more than one publication (n = 2).40,41 A nested patient cohort analysis from the AF Suppression Trials I, II and III (AFIST) was also excluded, since the primary goal of these studies was to determine the impact of different anti-arrhythmic strategies (amiodarone, etc.) on the incidence of AF after cardiac surgery, with ∼45% of enrolled patients being randomized to a prophylactic oral amiodarone therapy before surgery.42

Figure 1

Flow diagram of the systematic literature search indicating the inclusion and exclusion process of studies.

After critical appraisal, 19 unique studies published between the years 1999 and 2007 fulfilled our eligibility criteria for meta-analysis inclusion, reporting the influence of a preoperative statin therapy on desired clinical outcomes in a total of 31 725 cardiac surgery patients. Three studies were RCT,4,8,15 three studies used a prospective4345 and 13 a retrospective design.914,16,4651 Seventeen of the 19 included trials were full-text publication, whereas from the remaining two studies presented at a scientific meeting between 2005 and 2007, one was available in abstract form50 and the other one as an oral presentation with full video webcast.47

Table 1 summarizes the characteristics of the included studies. Of the 31 725 patients 17 201 (54.2%) patients were on preoperative statin therapy compared with 14 524 (45.8%) patients without statins. Fourteen studies focused on isolated CABG (92.0%; 29 198 patients), while five studies included patients undergoing isolated valve surgery (6.3%; 1990 patients) or both (1.7%; 537 patients). Elective surgery was performed in 82.2% (26 092) of patients and 98.7% (31 298) were primary procedures. Various statin types, dosage, re-initiation regimens, and follow-up periods were used. Although one study examined the effects of preoperative lipid-lowering therapy rather than statin therapy on postoperative outcomes,12 the vast majority of these patients received statins (86%) compared with other lipid lowering agents (14%) before surgery and, therefore, this report was included in our systematic review.

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Table 1

Characteristics of included studies (n = 19)

ReferenceStudy designStudy populationSize (age)Statin/no statinExposure (days)Statin type; dose; re-initiationReported outcomesFollow-up (days)QoS**
Christenson15RCTIsolated CABG; 87% elective77 (63)40/3728Simvastatin; 20 mg/daily; NRIn-hospital mortality, Myocardial infarction, Renal failure, LOS in hospital71/22
Dotani et al.46RetrospectivePrimary, isolated, elective CABG323 (63)104/21980% long-term use, 20% <3 days80% atorvastatin, 11% simvastatin, 6% lovastatin, 3% pravastatin 1% fluvastatin;10-20 mg/daily; remained on statinsCardiac death, Myocardial infarction, Arrhythmias, Stroke60–/22
Pan et al.10RetrospectivePrimary, isolated CABG; 84% elective1663 (63)943/720–*Atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin; NR; NR30-day mortality, Myocardial infarction, Arrhythmias, Stroke, Renal failure30–/20
Ali et al.14RetrospectiveCABG (80%), valve surgery (11%) or both (9%); 87% elective5469 (NR)3555/1914–*NR; NR; NRIn-hospital mortality, Myocardial infarction, Stroke, LOS in hospital7–/23
Subramanian et al.50 (abstract, 2005)RetrospectivePrimary, isolated CABG; 97% elective1308 (66)654/654–*NR; NR; NRIn-hospital mortality, Atrial arrhythmiasNR–/21
Aboyans et al.45Prospective observationalIsolated CABG; 83% elective810 (66)455/355>28 days45% pravastatin, 21% simvastatin, 20% atorvastatin, 12% cerivastatin, 2% fluvastatin; NR; NRStroke30–/19
Chello et al.4RCTPrimary, isolated, elective CABG40 (65)20/2021Atorvastatin; 20 mg/daily; NRIn-hospital mortality, Myocardial infarction, Stroke, Atrial fibrillation, Renal failure73/24
Clark et al.9RetrospectiveElective CABG with or without valve surgery (80%); isolated valve surgery (20%)3829 (63)1044/2785–*40% atorvastatin, 44% simvastatin, 7% lovastatin, 6% pravastatin, 3% fluvastatin; 10–60 mg/daily; NR30-day mortality30–/20
Collard et al.11RetrospectivePrimary, isolated, elective CABG2666 (63)1352/1314–*Atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin; NR; NRIn-hospital mortality, Myocardial infarctionUntil discharge–/22
Marin et al.43Prospective, observationalPrimary, isolated, elective CABG234 (65)144/9031NR; NR; NRAtrial fibrillationUntil discharge–/17
Pascual et al.44Prospective, observationalPrimary, isolated, elective CABG141 (65)87/543641% atorvastatin, 28% simvastatin, 31% pravastatin; NR; NR30-day mortality, Myocardial infarction30–/21
Patti et al.8RCTElective CABG with (21%) or without (79%) valve surgery200 (66)101/997Atorvastatin; 40 mg/daily; given until discharge30-day mortality, Myocardial infarction, Atrial fibrillation, LOS in hospital305/28
Coleman et al.16RetrospectiveCABG (29%), valve surgery (34%) or both (37%); 52% elective1934 (66)1248/686–*NR; NR; NRIn-hospital mortality, Infection rate6 (median)–/18
Magovern et al.47 (presentation, 2007)RetrospectiveIsolated CABG; 42% elective2377 (65)1004/1373–*NR; NR; NRIn-hospital mortalityUntil discharge–/20
Maricalsco et al.48RetrospectivePrimary, isolated CABG; 76% elective405 (66)218/1874638% atorvastatin, 44% simvastatin, 18% other; mean dose 22 mg/ daily; NRIn-hospital mortality, Myocardial infarction, Atrial fibrillation8–/22
Oyzadin et al.49RetrospectivePrimary, elective CABG with (2%) or without (98%) valve surgery362 (61)267/95>6044% atorvastatin, 26% simvastatin, 20% fluvastatin, 10% pravastatin; mean dose 27 mg/daily; given after surgeryAtrial fibrillation7–/18
Powell et al.12RetrospectivePrimary, isolated CABG; 84% elective4739 (67)2334/2405<3086% on statins (14% on other lipid-lowering therapy); NR; NRIn-hospital mortality, Stroke, Atrial fibrillationUntil discharge–/23
Tabata et al.51RetrospectiveIsolated CABG; 40% elective1802 (66)1039/763–*54% atorvastatin, 39%, simvastatin 4% pravastatin, 3% other; 5-80 mg/daily; statins for both groups after surgeryRenal failureNR–/19
Thielmann et al.13RetrospectivePrimary, isolated, elective CABG3346 (66)2592/754–*Atorvastatin, simvastatin, lovastatin, pravastatin, fluvastatin; cerivastatin; NR; NRIn-hospital mortality, Myocardial infarction, Arrhythmias, Stroke, Renal failure8–9–/22
  • Key characteristics of studies including design, type of surgery, sample size and mean age of patient groups, preoperative statin exposure (mean days), statin therapy regimen and measured outcomes during the postoperative follow-up period (mean days). CABG, coronary artery bypass grafting; LOS, length of stay; NR, not reported; RCT, randomized controlled trial. *Taking statins preoperatively; **Quality assessment of included studies with the Jadad [only for RCT; total score from 0 (poor) to 5 (excellent)] and the Downs and Black score [total score from 0 (poor) to 29 (excellent)].

Quality of included studies

The Jadad quality score was 5 (excellent), 3 (good) and 1 (poor) for the three RCT, respectively (Table 1). Overall the 19 studies were rated as being of good quality with an average Downs and Black score of 21.1 ± 2.5 (range 17–28 points); only five studies scored below 20 points. However, scores for internal validity bias and confounding averaged 4.8 ± 0.9 and 3.7 ± 0.9, respectively, indicating the lack of randomization and blinding in the included trials. Study quality ratings correlated significantly (P < 0.05) between the two independent investigators with a Spearman correlation coefficient of 0.94.

Clinical outcomes

Short-term mortality

Fifteen studies with 28 517 patients investigated the association between preoperative statin therapy and early all-cause mortality.4,816,44,4648,50 One trial that reported mortality after a follow-up period of 60 days was also included in this meta-analysis.46 No significant heterogeneity was observed between these studies (P = 0.30; I2 = 14.6%; Figure 2) and overall incidence of short-term mortality was 2.9%. Mortality was significantly lower (2.2 vs. 3.7%, P < 0.0001; Table 2) in patients undergoing cardiac surgery who received preoperative statin therapy compared with controls, with an absolute risk reduction of 1.5%. Our meta-analysis revealed a 43% reduction in the odds of short-term mortality (OR 0.57; 95%CI: 0.49–0.67; P < 0.0001 for overall effect) in patients receiving statins before cardiac surgery.

Figure 2

Forest plot of retrieved studies evaluating preoperative statin use and the incidence of early all-cause mortality after cardiac surgery. OR, odds ratio; CI, 95% confidence interval.

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Table 2

Incidence of clinical outcomes

OutcomeSample size (N)Treatment group % (N)Incidence % (N)Absolute RR%χ2 test (P-value)
Mortality28 517Statin: 53.6% (15 296)2.2% (340)1.5%<0.0001
Control: 46.4% (13 221)3.7% (490)
Myocardial infarction14 330Statin: 62.9% (9012)4.2% (380)−0.3%0.373
Control: 37.1% (5318)3.9% (208)
Atrial fibrillation7643Statin: 52.7% (4027)24.9% (1004)4.3%<0.0001
Control: 47.3% (3616)29.2% (1056)
Stroke16 390Statin: 61.0% (10 003)2.1% (212)0.8%0.001
Control: 39.0% (6387)2.9% (187)
Renal failure6408Statin: 66.1% (4236)3.9% (165)0.6%0.275
Control: 33.9% (2172)4.5% (97)
  • Comparison of the incidence of analysed clinical outcomes in patients with (Statin) or without (Control) preoperative statin treatment. N, number of patients; RR, risk reduction.

Myocardial infarction

An overall MI incidence of 4.1% was reported in 10 studies (14 330 patients; Table 2).4,8,10,11,1315,44,46,48 There was no significant heterogeneity among the included studies (P = 0.12; I2 = 37.6%; Figure 3). Pooled results showed no significant reduction in the incidence of MI between patients with or without preoperative statin therapy (4.2 vs. 3.9%; P = 0.373; OR 1.11; 95%CI: 0.93–1.33; P = 0.25 for overall effect).

Figure 3

Forest plot of retrieved studies evaluating preoperative statin use and the incidence of myocardial infarction after cardiac surgery. OR, odds ratio; CI, 95% confidence interval.

Atrial fibrillation

A 26.9% overall incidence rate of postoperative AF was reported in a total of 7643 patients from seven analysed studies (Table 2),4,8,10,12,43,48,49 with only three studies reporting new-onset AF.8,48,49 Therefore, significant heterogeneity observed between studies (P = 0.003; I2 = 69.6%) was accounted for by employing a random effect analysis (Figure 4). Preoperative statin therapy resulted in a 4.3% absolute risk reduction in AF (24.9 vs. 29.2%; P < 0.0001) and a 33% reduction in the odds for AF in cardiac surgery patients (OR 67; 95%CI: 0.51–0.88; P = 0.004 for overall effect).

Figure 4

Forest plot of retrieved studies evaluating preoperative statin use and the incidence of atrial fibrillation after cardiac surgery. OR, odds ratio; CI, 95% confidence interval.

Stroke

Seven studies including 16 390 patients examined the association between preoperative statin therapy and stroke.4,10,1214,45,46 No heterogeneity was observed between these studies (P = 0.10; I2 = 45.1%; Figure 5) and overall stroke incidence was 2.4%. Stroke rate was lower (2.1 vs. 2.9%, P = 0.001; Table 2) in patients who received statin therapy before cardiac surgery compared with controls. Statin therapy was associated with a 26% reduction in the odds for stroke (OR 0.74; 95%CI: 0.60–0.91; P = 0.004 for overall effect).

Figure 5

Forest plot of retrieved studies evaluating preoperative statin use and the incidence of stroke after cardiac surgery. OR, odds ratio; CI, 95% confidence interval.

Renal failure

Five studies included in this meta-analysis reported an incidence of 4.1% for renal failure in a total of 6408 patients (Table 2).4,10,13,15,51 Significant heterogeneity was observed among these studies (P = 0.05; I2 = 58.3%; Figure 6) and preoperative statin therapy was not associated with a significant reduction in the odds (OR 0.78; 95%CI: 0.46–1.31; P = 0.34 for overall effect) or incidence (3.9 vs. 4.5%; P = 0.275) for renal failure.

Figure 6

Forest plot of retrieved studies evaluating preoperative statin use on the incidence of renal failure after cardiac surgery. OR, odds ratio; CI, 95% confidence interval.

Preoperative group characteristics

In an attempt to identify possible differences between groups, pooled preoperative prevalence was calculated for female gender, history of MI, diabetes, hyperlipaemia, renal failure, use of ß-blockers and anti-platelet therapy (i.e. aspirin), and status of surgery (non-elective, off-pump). WMDs were determined for age, cardiopulmonary bypass (CPB) and aortic cross-clamp time (Table 3). Patients receiving preoperatively statins were more likely to be younger, of male gender, to have a previous MI, diabetes or hyperlipaemia and receive a ß-blocker or aspirin therapy before surgery (P < 0.001). In contrast, more patients without statins received non-elective surgery and surgery with CPB (P < 0.01), while no differences were observed in CPB and aortic cross-clamp durations.

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Table 3

Preoperative characteristics of patients

DichotomousSample size (N)Prevalence % (N)Treatment groups % (N)χ2 test (P-value)
Female gender30 68126.7% (8191)Statin: 25.2% (4186)<0.001
Control: 28.4% (4005)
MI history21 48743.0% (9237)Statin: 44.3% (5036)<0.001
Control: 41.5% (4201)
Diabetes28 30427.2% (7702)Statin: 29.4% (4590)<0.001
Control: 24.5% (3112)
Hyperlipaemia19 32367.5% (13 044)Statin: 87.6% (8812)<0.001
Control: 45.7% (4232)
Renal failure28 6947.6% (2177)Statin: 7.5% (1162)0.502
Control: 7.7% (1015)
ß-blocker22 43566.0% (14 799)Statin: 73.1% (8700)<0.001
Control: 57.9% (6099)
Aspirin19 98869.5% (13 882)Statin: 73.4% (7725)<0.001
Control: 65.0% (6157)
Non-elective surgery30 91517.8% (5497)Statin: 17.2% (2881)0.004
Control: 18.5% (2616)
Off-pump30 6811.9% (589)Statin: 2.4% (395)<0.001
Control: 1.4% (194)
ContinuousSample size (N)WMD95%CIP-value
Age (years)25 446−0.90−1.45 to −0.360.001
CPB time (min)17 918−1.10−3.79 to 1.590.42
AoX time (min)23 972−0.93−2.49 to 0.650.24
  • Comparison of the pooled dichotomous preoperative variables including female gender, history of myocardial infarction (MI), diabetes, hyperlipaemia, renal failure, status of surgery (non-elective, off-pump), ß-blockers and aspirin use in statin-treated patients (statin) or controls. For differences between pooled continuous variables: age, cardiopulmonary bypass (CPB) and aortic cross-clamp time (AoX) the weighted mean difference (WMD; (−) favours statin pretreated patients) with 95% confidence interval (CI) was determined. N, number of patients.

Publication bias

Assessment of publication bias using visual examination of the funnel plot (Figure 7) and Egger’s weighted regression statistic (P = 0.60) indicated no significant publication bias. The Trim-and-Fill method suggested that only one missing study was needed to achieve a symmetrical funnel plot. Inclusion of the missing study resulted in an adjusted OR of 0.60 (95%CI: 0.52–0.70) for the endpoint early all-cause mortality. Of note, studies with smaller weight tended towards larger effects as indicated by the wider distribution at the base of the funnel plot.

Figure 7

Funnel plot with solid circles representing actual included studies with their respective study weight (%). The Trim-and-Fill method suggested that only one missing study was needed to achieve a symmetrical funnel plot, as indicated by the open circle. The solid vertical line represents the unadjusted odds ratio (OR) for short-term mortality, and the dotted line indicates the recalculated adjusted OR after allowing for publication bias. SE, standard error.

Discussion

As the largest meta-analysis to date evaluating the impact of preoperative statin use on adverse clinical outcomes after cardiac surgery, our results suggest that statin pretreatment significantly reduces postoperative early all-cause mortality, and incidence of AF and stroke. Specifically, preoperative statin use was followed by a 1.5% absolute and 40% relative risk reduction in early all-cause mortality, thereby resulting in an estimated 67 patients needed to treat to avoid a death after cardiac surgery. The observed statin survival benefit is largely based on the outcome data of eight retrospective cohort studies, which contribute to ∼95% of the overall weight for this endpoint,914,16,47 and exceeds the relative risk reduction reported for long-term statin use after CABG.1 On the other hand, included prospective trials were underrepresented in our analysis with a negligible overall impact on the treatment effect. However, the effective sample size of our review with improved statistical power resulted in the observed reduction of early all-cause mortality in favour of statins, that persisted even after correcting for possible publication bias (OR: 0.60; 95%CI: 0.52–0.70). Our review therefore adds important evidence that may settle the ongoing controversies arising from previous cardiac surgery trials. For instance, in two recent reports statin use prior to cardiac surgery failed to decrease all-cause in-hospital mortality.11,13 Conversely, Clark et al.9 reported a substantial decrease in 30-day mortality in statin pretreated patients, that remained evident even after risk-adjustment of patients groups (OR: 0.55; 95%CI: 0.32–0.93), thereby closely resembling the results shown by the present meta-analysis. The validity of our pooled data analysis is further supported by the largest retrospective study to date,7 that showed a similar ∼1–2% absolute risk reduction and ∼40% reduction in the odds of all-cause mortality for statin pretreated patients following predominantly major non-cardiac surgery.

In addition, our meta-analysis of the incidence of postoperative AF and stroke demonstrated a 4.3 and 0.8% absolute risk reduction, and a 15 and 28% relative risk reduction in patients receiving statins preoperatively, respectively. Although the variable definition of postoperative AF, including type of AF (new-onset, any AF), monitoring modalities and anti-arrhythmic strategies are clearly accountable for the heterogeneity among studies, the overall statin effect shown by our meta-analysis is consistent with the findings of the ARMYDA-3 trial, that reported a 61% reduction in the odds for new-onset AF in patients randomly allocated to statin treatment before cardiac surgery.8 Indeed, the positive impact of statin pretreatment on postoperative new-onset AF is probably underestimated in our review, since failure to detect a difference between treatment groups by two retrospective trials10,12 that contribute to ∼46% of the overall weighting for this endpoint, is probably attributed to the fact that any postoperative AF, irrespective of type, was recorded in these trials. Recalculated pooled effects after exclusion of these reports would have resulted in a 50% reduction in the odds for postoperative AF (OR 0.50, 95%CI: 0.39–0.65; P < 0.0001) in statin pretreated patients, thereby approximating closely the results of the ARMYDA-3 trial.8

For the clinical endpoint stroke, the incidence of 2.4% in our combined patient population is in agreement with the ∼2–3% estimated stroke risk for patients aged between 60 and 70 years undergoing CABG.52 Only one prospective45 and retrospective trial,14 respectively, demonstrated a favourable impact of preoperative statin use on stroke. In contrast to this, our meta-analysis strengthens the evidence that statins prior to cardiac surgery reduce the incidence of stroke. This important finding is further supported by previous reports, demonstrating a ∼three-fold reduction in the rate of cerebrovascular events after carotid endarterectomy in statin pretreated patients.53,54 When taking into consideration that the overall case fatality following post-CABG stroke is ∼25%,52 it seems plausible that the observed reduction of early all-cause mortality in statin pretreated patients might be partially attributed to their beneficial neuroprotective effects.

The observed effect of statin therapy on the incidence of MI after cardiac surgery is less clear. Pooled analysis failed to delineate a beneficial effect on MI, despite the overwhelming evidence for cardioprotective statin actions given by secondary prevention trials1,2 or after major non-cardiac surgery.55 This difference may be attributed to several factors, including the poor standardization in the perioperative statin therapy regimen (dose, duration, and reintroduction) of included studies. In this regard, prospective trials with well-controlled statin reintroduction after surgery were associated with a lower incidence of MI when compared with retrospective studies.15,44 This assumption is also supported by the report of Collard et al.,11 showing that postoperative statin withdrawal after cardiac surgery is linked with an increased risk of cardiac mortality. Thus, the definite impact of preoperative statins on MI in the acute setting of cardiac surgery remains to be elucidated. Similarly, our review of the literature does not support the evidence for renoprotective effects of statins after cardiac surgery. However, the fewest studies focused on this endpoint and significant heterogeneity was present among studies, probably due to variable definitions for renal insufficiency. It is noteworthy, that the only study investigating new-onset of renal failure as the primary endpoint, revealed a 61% reduction in the odds for renal failure in propensity-matched cohorts after CABG.51 However, the results of this study are largely limited by its retrospective nature.

As with any meta-analysis, our review has several limitations that must be considered for accurate interpretation of the reported treatment effects. First, our analysis revealed an unequal distribution of potential confounding factors among pooled treatment groups with, most importantly, statin pretreated patients having a higher prevalence of ß-blocker and aspirin therapy before surgery. This treatment bias indicates a more aggressive management of risk factors and superior cardioprotection in statin pretreated patients with unknown impact on the estimated effects presented in this review. Further, our study was unable to distinguish whether lipid-lowering or pleiotropic actions were responsible for the observed treatment effects due to poor reporting of preoperative patient lipid status. Secondly, our meta-analysis is limited by the scarcity of evidence for statins from randomized trials. Thus, inclusion of retrospective trials resulted in a high variability of used statin agents, dose, and treatment regimens that may account for the heterogeneity among studies. However, proper methods of study selection and analysis of pooled data in accordance with the QUORUM guidelines and current recommendations for meta-analysis of observational trials were employed to address this issue and publication bias was excluded by funnel plot analysis and Eggers’ statistics, making the over-representation of published literature that report a positive statin effect unlikely. Lastly, our review did not account for differences in study quality, since all included studies were rated as being of moderate to good methodological quality.

In conclusion, our systematic review demonstrates a substantial improvement in early clinical outcome for statin pretreated patients undergoing cardiac surgery. Although the results from our review is supported by an effective sample size, adding up over 30 000 cardiac surgery patients, interpretation towards an empirical use of statins for all patients undergoing cardiac surgery seems premature, until evidence from future randomized trials is sufficiently accumulated. Nevertheless, we believe that it is reasonable and in compliance with existing guidelines21 to advocate an intensified preoperative statin treatment, followed by a rigorous postoperative re-initiation regimen, in all hyperlipaemic patients with multiple cardiac risks and coronary heart disease scheduled for cardiac surgery.

Acknowledgements

The authors would like to thank Dr Aman Mahajan (Department of Anesthesiology, Division of Cardiothoracic Anesthesia, University of California, Los Angeles, CA, USA) for his editorial assistance.

Conflict of interest: the authors have no conflicts of interest to declare.

References

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