Preoperative statin therapy reduces postoperative all-cause mortality in cardiac surgery: A meta-analysis of controlled studies

Two recent meta-analyses1Kapoor A.S. Kanji H. Buckingham J. Devereaux P.J. McAlister F.A. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies.BMJ. 2006; 333: 1149Crossref PubMed Scopus (116) Google Scholar, 2Hindler K. Shaw A.D. Samuels J. Fulton S. Collard C.D. Riedel B. Improved postoperative outcomes associated with preoperative statin therapy.Anesthesiology. 2006; 105: 1260-1272Crossref PubMed Scopus (226) Google Scholar demonstrated that postoperative mortality was significantly lower in patients undergoing cardiac surgery who received preoperative statin therapy than in those who did not. The meta-analysis by Kapoor and associates,1Kapoor A.S. Kanji H. Buckingham J. Devereaux P.J. McAlister F.A. Strength of evidence for perioperative use of statins to reduce cardiovascular risk: systematic review of controlled studies.BMJ. 2006; 333: 1149Crossref PubMed Scopus (116) Google Scholar however, included merely 4 published articles, and that by Hindler and colleagues2Hindler K. Shaw A.D. Samuels J. Fulton S. Collard C.D. Riedel B. Improved postoperative outcomes associated with preoperative statin therapy.Anesthesiology. 2006; 105: 1260-1272Crossref PubMed Scopus (226) Google Scholar cited 4 published articles and 3 scientific abstracts. Therefore, the appropriate role of preoperative statin therapy in cardiac surgery remains unclear. Furthermore, several controlled studies of preoperative statin therapy in cardiac surgery have been published to date since the 2 meta-analyses were conducted. Herein, we performed a meta-analysis of controlled studies of preoperative statin therapy for prevention of postoperative all-cause mortality in cardiac surgery. All controlled studies (English-language full-text journal publications excluding scientific abstracts) of preoperative statin therapy in cardiac surgery were identified by a 2-level search strategy. First, a public domain database (MEDLINE) was searched using a Web-based search engine (PubMed). Second, relevant studies were identified through a manual search of secondary sources including references of initially identified articles and a search of reviews and commentaries. The MEDLINE database was searched from January 1966 to December 2007. MeSH keywords included “Hydroxymethylglutaryl-CoA Reductase Inhibitors” and “Cardiac Surgical Procedures.” Studies considered for inclusion met the following criteria: the design was a controlled study of preoperative statin therapy; the study population was patients undergoing cardiac surgery; and main outcomes included postoperative all-cause mortality. Data regarding detailed inclusion criteria and mortality were abstracted (as available) from each individual study. For each study, data regarding mortality in both the statin and control (placebo or no statin) groups were used to generate crude odds ratios (ORs) and 95% confidence intervals (CIs). We also abstracted adjusted ORs and 95% CIs for mortality if reported. Study-specific estimates were combined using inverse variance-weighted averages of logarithmic ORs in a random-effects model. Between-study heterogeneity was analyzed by means of standard χ2 tests. Publication bias was assessed mathematically using an adjusted rank-correlation test. Our search identified 13 controlled studies of preoperative statin therapy in cardiac surgery, the majority of which was coronary artery bypass graft surgery (Table 1). These included 3 randomized controlled trials,3Christenson J.T. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG.Eur J Cardiothorac Surg. 1999; 15: 394-400Crossref PubMed Scopus (99) Google Scholar, 4Chello M. Patti G. Candura D. Mastrobuoni S. Di Sciascio G. Agrò F. et al.Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med. 2006; 34: 660-667Crossref PubMed Scopus (194) Google Scholar, 5Patti 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 undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study.Circulation. 2006; 114: 1455-1461Crossref PubMed Scopus (527) Google Scholar 3 prospective cohort studies, and 7 retrospective cohort studies. Pooled analysis of crude ORs from all 13 studies (representing 19,542 patients) demonstrated a statistically significant 45% reduction in postoperative all-cause mortality with preoperative statin therapy relative to control (pooled crude OR, 0.55; 95% CI, 0.46–0.66; P < .01). There was neither study heterogeneity of results (P = .64) nor evidence of significant publication bias (P = .74). Six of the 10 observational studies reported adjusted ORs for mortality by multivariate analysis or propensity score matching. When adjusted ORs from these 6 observational studies and ORs from the 3 randomized controlled trials3Christenson J.T. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG.Eur J Cardiothorac Surg. 1999; 15: 394-400Crossref PubMed Scopus (99) Google Scholar, 4Chello M. Patti G. Candura D. Mastrobuoni S. Di Sciascio G. Agrò F. et al.Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med. 2006; 34: 660-667Crossref PubMed Scopus (194) Google Scholar, 5Patti 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 undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study.Circulation. 2006; 114: 1455-1461Crossref PubMed Scopus (527) Google Scholar were pooled (representing 18,637 patients), preoperative statin therapy was associated with a 25% reduction in mortality relative to control that remained statistically significant (pooled adjusted OR, 0.76; 95% CI, 0.64–0.90; P < .01). There was neither study heterogeneity of results (P = .60) nor evidence of significant publication bias (P = .53). Pooled analysis of ORs and adjusted Ors, respectively, from 2 randomized controlled trials3Christenson J.T. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG.Eur J Cardiothorac Surg. 1999; 15: 394-400Crossref PubMed Scopus (99) Google Scholar, 4Chello M. Patti G. Candura D. Mastrobuoni S. Di Sciascio G. Agrò F. et al.Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med. 2006; 34: 660-667Crossref PubMed Scopus (194) Google Scholar and 3 observational studies that enrolled patients undergoing coronary artery bypass graft surgery exclusively (representing 7205 patients) demonstrated a statistically significant 41% reduction in mortality with preoperative statin therapy relative to control (adjusted OR, 0.59; 95% CI, 0.36–0.97; P = .04). There was neither study heterogeneity of results (P = .57) nor evidence of significant publication bias (P = .62).Table 1Characteristics and outcomes of included studiesOR (95% CI) for mortalityAuthorPublicationDesignSample sizeType of operationCrudeAdjustedAli and ButhInt J Cardiol. 2005;103:12-8Retrospective cohort5,469Cardiac surgery (Isolated CABG 80%)0.50 (0.38–0.67)0.87 (0.61-1.25)∗Propensity score matching.Chello et al4Chello M. Patti G. Candura D. Mastrobuoni S. Di Sciascio G. Agrò F. et al.Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med. 2006; 34: 660-667Crossref PubMed Scopus (194) Google ScholarCrit Care Med. 2006;34:660-7Randomized controlled40Elective isolated CABG1.00 (0.02–52.85)Christenson3Christenson J.T. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG.Eur J Cardiothorac Surg. 1999; 15: 394-400Crossref PubMed Scopus (99) Google ScholarEur J Cardiothorac Surg. 1999;15:394-400Randomized controlled77Elective isolated CABG0.93 (0.02–47.85)Clark et alJ Thorac Cardiovasc Surg. 2006;131:679-85Retrospective cohort3,829Elective cardiac surgery (any CABG 81%)0.43 (0.28–0.66)0.51 (0.27-0.94)∗Propensity score matching.Coleman et alCurr Med Res Opin. 2007;23:1783-90.Retrospective cohort1,934Cardiac surgery (isolated CABG 63%)0.68 (0.45–1.03)0.80 (0.64-0.99)†Multivariate analysis.Collard et alJ Thorac Cardiovasc Surg. 2006;132:392-400Prospective cohort2,666Elective primary isolated CABG0.79 (0.47–1.33)0.04 (0.08-0.93)†Multivariate analysis.Dotani et alAm J Cardiol. 2000;86:1128-30, A6Retrospective cohort323Elective isolated CABG0.12 (0.01–2.08)NRLiakopoulos et alThorac Cardiovasc Surg. 2006;54:250-4Prospective cohort36Elective isolated CABG1.00 (0.02–53.12)NRMariscalco et alAnn Thorac Surg. 2007;84:1158-64Retrospective cohort405Elective primary isolated CABG0.28 (0.01–7.03)NRPan et alCirculation. 2004;110(11 Suppl 1):II45-9Retrospective cohort1,663Primary isolated CABG0.47 (0.25–0.87)0.58 (0.31–1.09)∗Propensity score matching.Pascual et alAnn Thorac Surg. 2006;81:78-83Prospective cohort141Elective isolated CABG0.16 (0.03–0.79)NRPatti et al5Patti 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 undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study.Circulation. 2006; 114: 1455-1461Crossref PubMed Scopus (527) Google ScholarCirculation. 2006;114:1455-61Randomized controlled200Elective cardiac surgery (isolated CABG 79%)0.98 (0.14–7.10)Thielmann et alJ Thorac Cardiovasc Surg. 2007;134:1143-9Retrospective cohort2,759Elective primary isolated CABG1.08 (0.39–3.00)1.18 (0.36–3.87)∗Propensity score matching.Total19,5420.55 (0.46–0.66)‡Pooled estimate using a random-effects model.0.76 (0.64–0.90)‡Pooled estimate using a random-effects model.OR, Odds ratio; CI, confidence interval; CABG, coronary artery bypass graft surgery; NR, not reported.∗ Propensity score matching.† Multivariate analysis.‡ Pooled estimate using a random-effects model. Open table in a new tab OR, Odds ratio; CI, confidence interval; CABG, coronary artery bypass graft surgery; NR, not reported. The present meta-analysis of 13 controlled studies demonstrated that preoperative statin therapy reduced postoperative all-cause mortality in cardiac surgery. The analysis, however, included 10 observational studies but merely 3 small randomized controlled trials (sample size: 40, 77, and 200).3Christenson J.T. Preoperative lipid-control with simvastatin reduces the risk of postoperative thrombocytosis and thrombotic complications following CABG.Eur J Cardiothorac Surg. 1999; 15: 394-400Crossref PubMed Scopus (99) Google Scholar, 4Chello M. Patti G. Candura D. Mastrobuoni S. Di Sciascio G. Agrò F. et al.Effects of atorvastatin on systemic inflammatory response after coronary bypass surgery.Crit Care Med. 2006; 34: 660-667Crossref PubMed Scopus (194) Google Scholar, 5Patti 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 undergoing cardiac surgery: results of the ARMYDA-3 (Atorvastatin for Reduction of MYocardial Dysrhythmia After cardiac surgery) study.Circulation. 2006; 114: 1455-1461Crossref PubMed Scopus (527) Google Scholar In an attempt to correct for and minimize selection bias, which exists in observational studies, related to statin use, we pooled adjusted instead of crude ORs from the observational studies and ORs from the randomized controlled trials, resulting in a statistically significant benefit of preoperative statin therapy for mortality in cardiac surgery or exclusive coronary artery bypass graft surgery. Nevertheless, larger randomized controlled trials are needed to confirm our results. Until sufficient numbers of events will be accumulated by evidence from randomized controlled trials to provide a definitive answer, advocating routine preoperative statin therapy in cardiac surgery is premature.