Cardiac surgery offers excellent therapeutic options

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1 Current Evidence for Perioperative Statins in Cardiac Surgery Elmar W. Kuhn, MD,* Oliver J. Liakopoulos, MD,* Yeong H. Choi, MD, and Thorsten Wahlers, MD Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Cologne, Germany Cardiac surgery improves life expectancy and quality of life for the constantly ageing population in developed countries. Mediated by their lipid-dependent and lipidindependent mechanisms, statins are sought to provide benefit with regard to better outcomes after cardiac surgery. Current guidelines recommend statin use in patients undergoing coronary artery bypass grafting, while less evidence is available for patients referred to heart valve surgery. Optimal selection of statin drug and dosage including perioperative timing of statin therapy remains largely unknown, but results of ongoing metaanalyses and future randomized trials will add important evidence to guide perioperative statin treatment of cardiac surgery patients. (Ann Thorac Surg 2011;92:372 9) 2011 by The Society of Thoracic Surgeons Cardiac surgery offers excellent therapeutic options for aquired cardiac disease and remains the therapy of choice for advanced coronary artery disease or severe aortic valve stenosis. Nonetheless, patients undergoing cardiac procedures are still at significant risk for postoperative major adverse cardiovascular events. According to the recent Adult Cardiac Surgical Database Report 2010 of the European Association for Cardio- Thoracic Surgery [1], the in-hospital mortality for patients undergoing coronary artery bypass grafting (CABG) is 2.2% and 3.4% for patients undergoing isolated valve procedures. Mortality rates are stable over the past decade, despite significant increases in patients comorbidities due to substantial improvements in surgical techniques and perioperative care that are aimed at optimizing clinical outcomes of patients. Planning and execution of the operation have become personalized with regard to on-pump or off-pump procedures, minimally invasive approaches, and myocardial protection strategies. However, these advantageous developments are somehow abrogated by the presence of increasing comorbidities in the constantly ageing patient population thereby leading to a higher incidence of high-risk procedures. Thus, if outcomes among cardiac surgery patients are to be improved, implementation of better strategies to limit the risk for major adverse events after cardiac procedures is imperative. Statins have caught the interest of both basic researchers and clinicians over the past years. Statins competitively inhibit the 3-hydroxy 3-methylglutaryl-coenzyme A reductase that catalyzes the rate-limiting step in cholesterol synthesis and, consequently, reduce the concentration of mevalonate and further down-stream products *Both authors contributed equally to this review. Address correspondence to Dr Liakopoulos, Department of Cardiothoracic Surgery, Heart Center, University of Cologne, Kerpener Strasse 62, Cologne, Germany; oliver.liakopoulos@uk-koeln.de. (Fig 1) [2]. As a result, expression of low-density lipoprotein (LDL) receptors on hepatocytes is increased and uptake of LDL-cholesterol from the blood into the liver is augmented, thereby leading to a decrease of LDL in the blood. Because elevated LDL blood concentration is one of the major risk factors for the development and progression of coronary artery disease, statin therapy has become an inherent part of the primary and secondary prevention of cardiovascular disease [3]. But even irrespective of the patients initial lipid profile or other presenting characteristics, a meta-analysis of more than 90,000 participants demonstrated that statins reduce the incidence of major coronary events, myocardial revascularization, and stroke in a wide range of individuals [4]. Furthermore, high-risk patients with established coronary artery disease benefit from a statin therapy with regard to a significant reduction in all-cause mortality and stroke rates [5]. Therefore, current guidelines of the American College of Cardiology-American Heart Association and National Cholesterol Education Program recommend the use of statins patients with established coronary artery disease when serum LDL levels exceed 100 mg/dl [6]. Of note, a most recent review conducted by Taylor and colleagues [7] raises doubts about the usefullness of statins in the primary prevention of cardiovascular disease. Notably, people with a low cardiovascular risk profile do not clearly profit by statin therapy in terms of preventing cardiovascular events. Beyond their lipid-lowering actions, statins exert lipidindependent ( pleiotropic ) effects that offer additional cardiovascular protection [8, 9]. These effects may be beneficial for the prevention of plaque rupture and thrombotic occlusion in coronary artery disease by inhibition of inflammatory cascades, endothelial dysfunction, and platelet activation [10 14]. Evidence for potentially relevant effects of nonlipid statin actions is mainly driven by results from animal and cell culture studies and 2011 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg KUHN ET AL 2011;92:372 9 STATINS IN CARDIAC SURGERY 373 Fig 1. Inhibition of cholesterol biosynthesis by statins by blocking the key enzyme HMG-CoA-reductase. (CoA coenzyme A; HMG hydroxy-methylglutaryl.) various clinical trials. Accumulating evidence from randomized controlled trials have demonstrated the efficacy of a preoperative statin therapy in reducing periprocedural cardiovascular events after percutaneous coronary intervention and noncardiac surgery when compared with statin-naïve patients, thereby making a preoperative treatment with statins a promising approach to reduce postoperative morbidity and mortality in patients scheduled for cardiac surgery [15, 16]. However, in patients undergoing cardiac procedures results are conflicting, with several studies [17, 18] reporting a decrease in short-term mortality and major cardiovascular events including myocardial infarction, atrial fibrillation, stroke, and renal failure in patients receiving preoperative statins, while others have failed to show a beneficial effect of statins on these endpoints [19 22]. Statins for Patients Undergoing Coronary Artery Bypass Grafting The first study evaluating the effect of statins prior to coronary artery bypass graft surgery was published in 1999 by Christenson [20]. The investigators randomized 77 patients with symptomatic coronary artery disease and hypercholesterolemia to either lipid-control with simvastatin (40 patients) or control (37 patients) for a preoperative duration of 4 weeks. Statin intake resulted in a reduction of total cholesterol levels before CABG surgery. The incidence of postoperative thrombocytosis as the primary endpoint was significantly reduced in statin-treated patients, which was associated to a reduction of postoperative myocardial infarction and transient renal failure when compared with statin-naïve patients. One-year follow-up after myocardial revascularization revealed that the incidence of bypass graft lesions of patients in the simvastatin group was significantly lower compared with control [23]. These results initiated a broad investigation of statin effects on hypercholesteremic patients with coronary artery disease who were scheduled for myocardial revascularization. All patients included into this study suffered from hypercholesterolemia; however, even normolipemic patients appear to benefit from a statin therapy as shown by a recent trial. Mannacio and colleagues [17] randomized 200 patients with normal LDL-cholesterol levels (mean LDL range: 121 to 127 mg/dl) to treatment with rosuvastatin or placebo 1 week before CABG. Incidence of myocardial damage defined as an elevation of cardiac troponin I, myoglobin, and creatine kinase-mb was significantly lower in statin-treated patients when compared with the placebo group. The authors concluded that perioperative statin therapy may improve short-term and long-term results after CABG procedures in normolipemic patients. Similarly, Thielmann and colleagues [24] retrospectively analyzed the impact of statin intake in patients with different preoperative cholesterol levels. A large cohort of patients undergoing first-time elective coronary bypass grafting (3,346 patients) was subdivided into 3 groups consisting of patients with statin-untreated hyperlipemia (group 1, control), statin-treated hyperlipemia (group 2), and normolipemic patients without statin therapy (group 3). The authors found that statin-treated hyperlipemia reduced the risk of major cardiovascular events in CABG patients to similar levels of untreated normolipemic patients when compared with controls. Despite promosing results of these studies in favor of a preoperative statin therapy for patients scheduled for CABG, more robust data from large-scale RCTs that analyze the impact of a preoperative statin therapy on hard clinical outcomes including postoperative mortality are still lacking. The ARMYDA-3 trial [18], the largest randomized controlled trial in patients undergoing myocardial revascularization, could not find an influence of preoperative atorvastatin administration on mortality. In this trial, two-hundred patients were randomized to receive either atorvastatin (101 patients) or placebo (99 patients) 7 days before the operation. The study was clearly underpowered and failed to display any difference among groups with regard to postoperative mortality, but showed a significant reduction in the incidence of postoperative atrial fibrillation in statin-treated patients [18]. Mannacio and colleagues reported comparable results to the ARYMDA-3 trial in a more recent randomized clinical trial (RCT) of 200 CABG patients with random preoperative allocation to rosuvastatin or placebo for 7 days. In contrast, Pan and colleagues [25] were the first to report a significant reduction of postoperative mortality in statin-pretreatd patients. In a retrospective cohort study of patients undergoing CABG surgery the investigators compared 943 patients with antihyperlipemic therapy to 720 statin-naïve patients. Multivariate logistic regression anal-

3 374 KUHN ET AL Ann Thorac Surg STATINS IN CARDIAC SURGERY 2011;92:372 9 ysis revealed that statin treatment was independently associated with a reduced incidence of 30-day all-cause mortality. Even after propensity-matching, statin therapy turned out to be an independent predictor for a lower incidence of the composite endpoint consisting of 30-day all-cause mortality and stroke (7.1% vs 4.6%; p 0.05). This finding was supported by another retrospective cohort study [26] that found improved cardiovascular outcomes, including death after CABG, in patients with preoperative statin treatment when compared with patients without statin therapy. When considering that patients= outcome is significantly influenced by major postoperative complications including stroke, atrial fibrillation, and renal failure, various studies have focused on these endpoints. Aboyans and colleagues [27] investigated factors predicting the incidence of stroke in patients undergoing CABG surgery. Among other factors, they demonstrated a neuroprotective effect of statin intake with reduction in postoperative cerebrovascular events (odds ratio [OR] 0.26; 95% conficence interval [CI] 0.06 to 0.86). New-onset atrial fibrillation is a common complication after heart surgery and associated with elevated morbidity of patients. The impact of statins on the postoperative incidence of atrial fibrillation was presented in a recent meta-analysis of our group. This systematic review accumulated data from 3 RCT and 10 observational studies of more than 17,000 cardiac surgery patients. Preoperative statin use resulted in a 22% and 34% unadjusted odds reduction for atrial fibrillation (OR 0.78; 95% CI 0.67 to 0.90) or new-onset atrial fibrilliation (OR 0.66; 95% CI 0.51 to 0.84) after surgery. The beneficial statin actions on atrial fibrillation persisted after pooled analysis of riskadjusted treatment effects from RCT and observational trials [28]. These findings were supported by another recent meta-analysis conducted by Winchester and colleagues [29] showing a significant reduction in the occurrence of post-cabg atrial fibrillation (OR 0.54; 95% CI 0.43 to 0.68) in statin-pretreated patients. Furthermore, the influence of statin therapy on success rates after surgical ablation for atrial fibrillation was evaluated in a prospective cohort study [30] on patients with (n 73) and without (n 76) preoperative statin therapy. All patients underwent on-pump cardiac procedures with concomitant surgical ablation for atrial fibrillation. Improved conversion rates were detected for statin-treated patients at discharge from hospital (p 0.07) and after 3 and 6 months (p 0.05 for both). Finally, renoprotective properties of statins have been reported by Tabata and colleagues [31] in a retrospective study of 1,802 CABG patients. The authors analyzed data from 641 matched cohorts of statin and non-statin patients and found a significant association between preoperative statin therapy and a lower incidence of postoperative renal insufficiency (OR 0.54; 95% CI 0.18 to 0.99). On the other hand, data from other studies could not demonstrate any benefit from a preoperative statin treatment with regard to mortality and morbidity in patients subjected to cardiac surgery. Ali and colleagues [19] assessed outcome variables of patients undergoing various types of cardiac surgery and analyzed the effect of preoperative statin use (3,555 patients) compared with no statin treatment (1,914 patients). The authors detected lower rates of mortality, stroke, and ventilation time, but this effect was not persistent after adjustment for relevant covariates that are known to impact cardiac surgical outcome. Similar to these findings, Powell and colleagues [32] found a benefit of statins in patients scheduled for CABG procedures in terms of lower mortality rates in a large patient cohort (2,334 patients on statins versus 2,405 patients not on statins), but failed to detect this difference after multivariate analysis. Additionally, Subramaniam and colleagues [22] evaluated the effect of statins on morbidity and mortality in patients after isolated CABG surgery in a large observational cohort study. Propensity-score matching of 654 patients per group revealed similar incidences of perioperative mortality, cardiac, neurologic, renal, and respiratory morbidity, and atrial fibrillation. In view of the limited clarity of available data and the absence of large RCTs, the most robust evidence for the effect of statin treatment prior to cardiac surgery is summarized in a comprehensive meta-analysis [33] that consisted of 31,725 patients undergoing predominately CABG procedures (92%). Statin pretreatment was associated with a substantial postoperative reduction in the odds of early mortality (OR 0.57; 95% CI 0.49 to 0.6), stroke (OR 0.74; 95% CI 0.60 to 0.91), and atrial fibrillation (OR 0.67; 95% CI 0.51 to 0.88) when compared with nontreated patients. The results of this systematic review in favor of a preoperative statin therapy in CABG patients strengthen the hypothesis that statins may play a beneficial role in the perioperative setting of CABG patients. This conclusion follows current guidelines of the European Society of Cardiology, American College of Cardiology, and the American Heart Association recommending that patients with established coronary artery disease undergoing CABG surgery should receive an intensified statin treatment (target LDL levels 100 mg/ dl) unless otherwise contraindicated [34]. Statins in Patients Undergoing Valve Surgery In contrast to the role of statins in CABG, that has been under extensive investigation for more than a decade, the role of statins for patients with valvular heart disease is less well defined. Compared with coronary artery disease, the linkage between elevated LDL-cholesterol blood levels and calcified aortic valve disease or bioprosthetic valve degeneration remains to be determined. Pohle and colleagues [35] showed that lipid-lowering therapy beneficially influences aortic valve degeneration. In their study, a cohort of 104 patients was subdivided into 2 groups, depending on LDL-levels. A higher progression of valve calcification was found during follow-up in patients with high cholesterol levels ( 130 mg/dl) when compared with patients with lower levels. Nonetheless, this study was limited by the fact that statin treatment was inhomogeneous among groups and overrepresented in patients showing lower progression of aortic calcification. Similarly, Farivar and colleagues [36]

4 Ann Thorac Surg KUHN ET AL 2011;92:372 9 STATINS IN CARDIAC SURGERY 375 found in patients needing valve replacement that cholesterol levels greater than 200 mg/dl were associated to a higher extent of aortic or mitral valve calcification (OR 3.9; 95% CI 1.7 to 8.9). Antonini-Canterin and colleagues [37] investigated the impact of statins on the progression of degenerative aortic valve stenosis. Analysis of the change in peak aortic velocity by echocardiography during follow-up examinations demonstrated a slower progression of aortic stenosis in patients treated with statins compared with untreated individuals. Seven studies assessing the effect of statin intake on progression of aortic stenosis were summarized in a systematic review reporting data from 405 statin-treated and 642 statin-untreated patients with aortic valve stenosis [38]. After a pooled analysis of the treatment effect of statins versus control, the investigators demonstrated a benefit of a statin therapy with regard to aortic jet velocity and deterioration of aortic valve area. The most comprehensive evidence for the role of statins and the progression of nonrheumatic calcific aortic stenosis was provided by a meta-analysis by Parolari and colleagues [39] who reviewed 10 studies (7 non-rcts, 3 RCTs) with a total of 3,822 patients. The authors found neither any marked difference with regard to all-cause (OR 0.98; 95% CI 0.74 to 1.30) or cardiovascular (OR 0.79; 95% CI 0.54 to 1.15) mortality, nor to the need for aortic valve surgery (OR 0.92; 95% CI 0.76 to 1.10) between both groups. Statin therapy had no impact on the progression of peak aortic jet velocity and mean aortic pressure gradient. The potential impact of statins on reduction of bioprosthetic valve degeneration after aortic valve replacement was investigated by Kulik and colleagues [40]. In this study, a total of 1,193 participants were followed for a mean duration of 4.5 years by echocardiographic reexaminations. The cohort contained 150 patients who received lipid-lowering therapy including statins (95.9%) early after surgery. Compared with patients without lipid-lowering therapy, the authors could not detect any beneficial effect of statins on the progression of structural valve deterioration in terms of increase of transprosthetic pressure gradients ( mm Hg vs mm Hg; p 0.87) or 10-year freeedom from reoperation (98.9% vs 95.4%; p 0.72). A longer follow-up with an extension of participants would have been desirable when taking into account the large number of patients treated with bioprosthetic aortic valve replacement, as this observation serves only as a short-term outlook. Experimentally, Lorusso and colleagues [41] tested the effect of statin administration on post-implant structural changes of bovine pericardial tissue. Bovine pericardial fragments were implanted subcutaneously in mice before animals were randomly allocated to statin treatment or to control. After 1.5 months, the authors detected less calcium content, reduced inflammation, and a lower extent of tissue injury of pericardial valves in statintreated animals. The question whether or not statins prevent bioprosthetic aortic valve degeneration after surgical valve replacement was addressed by Gilmanov and colleagues [42] in a recent literature review, with the final conclusion that current clinical evidence for a beneficial effect of statins is insufficient. Paraskevas and Mikhailidis [43] confirm the findings of Gilmanov and colleagues literature review, but recommend routine statin use for patients undergoing aortic valve replacement due to their potentially beneficial pleiotropic effects, despite contradictory results from retrospective studies. This recommendation was mainly based on several reports, including a retrospective study of 447 patients undergoing valvular procedures by Fedoruk and colleagues [44]. Of those, 203 patients received statins perioperatively and the remainder did not. Patients in the statin-group presented with more comorbidities, including preoperative stroke, diabetes, cerebrovascular disease, and dyslipemia. However, the incidence of a composite endpoint consisting of death, stroke, and renal failure was lower in patients with statin treatment, suggesting beneficial perioperative pleiotropic effects (OR 1.9; 95% CI 0.96 to 3.76). The authors postulated the need for a randomized controlled trial to further elucidate this aspect. Likewise, Tabata and colleagues [45] reported data from 1,389 patients undergoing cardiac valve surgery with 363 patients taking statins preoperatively. Operative mortality rate and the incidences of stroke and perioperative myocardial infarction were not markedly lower for patients in the statin group than for statin-naïve patients, but generalized estimating equations showed that preoperative statin intake correlated significantly with lower mortality for statin-patients (OR 0.25; 95% CI 0.12 to 0.54). However, the groups were heterogeneous with regard to preoperative risk profile and preoperative medication. In conclusion, current evidence for patients with degenerative valve disease and for patients with bioprosthetic valve replacement is limited and contradictory and does not support the routine use of statins. Conclusions should not be extrapolated from studies with focus on patient cohorts with isolated coronary artery disease until robust evidence is available from future trials addressing specifically heart valve disease. But importantly, statin therapy should not be withheld for an increasing number of patients scheduled for cardiac valve replacement procedures that present with hyperlipedemia and other risk factors for coronary artery disease in compliance with existing guidelines. Which Statin Should be Used in the Perioperative Period? All currently available statins reduce the biosynthesis of LDL-cholesterol by inhibition of 3-hydroxy 3-methylglutaryl-coenzyme A reductase to a different extent (Table 1). The dose-effect relationship seems to be most favorable for rosuvastatin with a reduction of 36% in LDLcholesterol for the lowest concentration [46]. However, it remains unclear from which statin an individual patient may benefit the most when taking into account their pleiotropic effects. Most studies evaluate the effect of a single statin making comparability of statins impossible, and restricting conclusions to the medication used in the specific trial. However, rosuvastatin and atorvastatin

5 376 KUHN ET AL Ann Thorac Surg STATINS IN CARDIAC SURGERY 2011;92:372 9 Table 1. Mean Reduction of Total Cholesterol With Different Statins and Doses a Statin 10 mg 20 mg 40 mg 80 mg Rosuvastatin 36% 40% 46% Atorvastatin 30% 35% 38% 46% Simvastatin 21% 26% 30% 37% Pravastatin 13% 18% 24% Fluvastatin 13% 19% 25% a Modified from Bullano and colleagues [46]. seem to offer the greatest advantage for patients undergoing cardiac procedures. This thesis is supported by studies from Tran and colleagues [47] and Ohsfeldt and colleagues [48] who analyzed the cost-effectiveness of commonly prescribed statins. The authors reported that rosuvastatin is the most cost-effective statin followed by atorvastatin, simvastatin, and pravastatin for patients with elevated lipid-levels. More patients with coronary heart disease who receive rosuvastatin compared with atorvastatin and simvastatin reached target LDL levels according to the current guidelines. And in a recent literature review published by Conway and Musleh [49] with special focus on CABG patients, the authors report about the superiority of rosuvastatin over other statins. Nevertheless, the beneficial pleiotropic actions of statins appear to be class dependent as they are mainly attributed to the reduced expression of downstream products of mevalonate [50]. Beyond the pleiotropic statin actions and selecting the most potent statin, it is important to keep in mind that the primary goal of statin therapy is the achievement of recommended LDL levels. This raises the question about the optimal statin dose. In 1,351 patients who had previous CABG surgery, the investigators of the Post-CABG trial [51] subdivided their cohort in an aggressive-treatment group (40 mg lovastatin per day) versus a moderate-treatment group (2.5 mg lovastatin per day) for 4.3 years on average. A significantly reduced progression of atherosclerosis in bypass grafts was observed in patients of the high-dose statin treatment arm with a 29% reduction of the incidence of revascularization compared with the group receiving moderate treatment (6.5% vs 9.2%; p 0.03). Furthermore, Cannon and colleagues [52] evaluated the incidence of a composite endpoint of death, myocardial infarction, unstable angina, revascularization, and stroke in more than 4,000 patients with acute coronary syndrome. The patients were randomly assigned to receive either 40 mg pravastatin or 80 mg atorvastatin and were followed-up for 3 years. A 16% reduction in the hazard ratio was recorded in favor of high-dose atorvastatin administration, reflecting a greater protection against death or major cardiovascular events compared with standard therapy. These results strengthen the need for continuous reevaluation of LDLcholesterol levels of patients subjected to statin treatment and eventually a readaptation of the statin dose. However, more important than readjusting a statin dose is the administration itself. Although statins represent a relatively safe class of drugs and are the most frequently prescribed medication worldwide, statins are still underutilized, especially in patients referred to CABG procedures [53, 54]. The possibility of adverse statin effects should be analyzed for each individual patient according to the preoperative risk profile; however, they occur relatively rarely and should be monitored. Statin side effects can be well managed if adeqaute therapeutic measures are implemented as summarized in the clinical advisory on statins published by the American College of Cardiology- American Heart Association [55]. Statin-treated patients may experience a reversible myopathy at a rate of 11 in 100,000 patient-years of follow-up and the incidence of rhabdomyolysis ranges at about 1 death per 1 million. In a small proportion of patients (1%) an increase of liver enzymes is noted that is predominantly reversible after statin withdrawl [53, 56, 57]. Despite the low-risk profile of statins, only about 50% of cardiac surgery patients admitted for surgical coronary revascularization receive statins and even less patients obtain sufficient lipid levels prior to coronary surgery in compliance with existing guidelines [58]. In clinical practice, optimal timing of (re-)administration of statins before and after cardiac surgery remains to be discussed as elevation of creatine kinase or liver enzymes due to reasons related to surgery may interfere with or obscure statin side effects. Furthermore, clinical signs such as myopathy can be misinterpreted as a complication of the surgical procedure (ie, pain from saphenectomy wound, etc) or statin intake and vice versa. However, the decision for a discontinuation of postoperative statin prescription should be well balanced, as the disadvantage of statin cessation was elucidated by Laufs and colleagues [59]. They showed an improvement of endothelial and vascular function after atorvastatin treatment in normocholesterolemic men that deteriorated as soon as statin therapy was withdrawn, irrespective of changes in cholesterol levels. Heeschen and colleagues [60] investigated the effect of statin withdrawal on death and nonfatal myocardial infarction in patients with acute coronary syndromes. Statin therapy reduced the event rate at 30-day follow-up when compared with patients without statin treatment, but discontinuation of statin therapy after hospitalization increased the cardiac risk rate to the level of statin-naïve patients. Similar to these findings, Collard and colleagues [61] investigated outcome data in 1,352 patients with and 1,314 without statin administration prior to CABG surgery. Preoperative statin use was associated with better survival; moreover, discontinuation of statin treatment after surgery was independently linked to an increased all-cause (0.60% vs 2.64%; p 0.01) and cardiac mortality at 30 days (0.45% vs 1.91%; p 0.01). Thus, non-discontinuation and early reinitiation (statin adminstration over nasogastric tube) of the preoperative statin regimen after cardiac surgery appears to be another key aspect for optimizing cardiovascular function in CABG patients.

6 Ann Thorac Surg KUHN ET AL 2011;92:372 9 STATINS IN CARDIAC SURGERY 377 Future Perspective There is little debate about the merit of statins in reducing the risk of cardiovascular disease, especially in patients with coronary artery disease. Statins have become a cornerstone in the medical therapy of atherosclerosis and secondary prevention including patients after surgical coronary revascularization. This is reflected in the recent guidelines with the highest level of evidence [34]. In addition, accumulating evidence suggests that preoperative statin administration seems to be associated with improved short-term patients outcome after cardiac surgery, but these recommendations are mainly based on results from a few, small RCTs and various observational studies that have been summarized in a recent systemtic review [33]. In view of the high number of patients undergoing cardiac surgery receiving a statin therapy, more evidence for clinical benefits associated with perioperative statin intake would be desirable, even though some smaller RCTs have been published in the meanwhile. Given the lack of large RCTs on this topic, a systematic review with meta-analysis is implemented by our group within the Cochrane Collaboration that is aimed to continuously evaluate the evidence for or against a statin therapy prior to cardiac surgery, with repeated updates of the growing body of evidence from future studies. The main focus will be to determine the effectiveness of a preoperative statin therapy on reduction of major adverse postoperative outcomes in patients undergoing cardiac surgery from all RCTs. Clinical endpoints will include in-hospital mortality and the postoperative incidence of myocardial infarction, atrial fibrillation, stroke, renal failure, length of stay on the intensive care unit and in-hospital-stay, as well as adverse drug events. Presumably, the finalized version of the first review will be available by the end of 2011 [62]. Furthermore, new evidence from animal models is emerging about some beneficial statin actions when given shortly before an ischemic event or at reperfusion. Mensah and colleagues [63] recorded infarct size of isolated rat hearts subjected to regional ischemia with various timing patterns of statin exposure. The authors observed reduced infarct sizes after atorvastatin treatment for 1 and 3 days, but this favorable effect remained undetectable after treatment for 1 and 2 weeks implicating a time-dependent loss of protection mediated by a chronic statin exposure. In 2 additional groups, atorvastatin was given for 1 and 2 weeks, respectively, with supplementary doses directly before post-ischemic heart reperfusion. These extra doses recaptured the protective effects of statins on infarct size when compared with chronic statin therapy alone. These experimental findings were transferred to the clinical scenario in patients undergoing percutaneous coronary interventions. The ARMYDA-RECAPTURE trial [15] randomized 383 patients with stable angina or acute coronary syndromes with preexisting chronic statin treatment ( 30 days) to either atorvastatin reloading therapy 12 hours and immediately before the procedure (192 patients) or placebo (191 patients). The 30-day incidence of a composite endpoint consisting of cardiac death, myocardial infarction, or unplanned revascularization occurred significantly more often in the placebo group than in the atorvastatin reloading group. Reloading therapy turned out to be an independent predictor for a lower incidence of the composite endpoint, with an 82% relative-risk reduction in patients with acute coronary syndromes. Unfortunately, there is no such randomized controlled trial for patients undergoing cardiac surgery or especially for those undergoing CABG procedures up to this date. However, these promising results probably could, in the same way, be verifiable in surgical patient cohorts where a controlled ischemia-reperfusion sequence is an essential part of on-pump procedures with cardioplegic cardiac arrest. A statin reloading regimen in patients scheduled for surgical revascularization would represent a promising approach optimizing perioperative outcomes of patients. In this context, the development of an intravenous statin solution, as requested by other investigators, would be highly desirable as it could offer new ways for perioperative statin administration in clinical practice, especially in critically ill patients undergoing cardiac surgery with inabililty of oral drug intake [64]. Apart from promising future strategies with regard to a statin reloading therapy or a intravenous statin solution, the essential problems of employing a beneficial statin therapy in clinical practice remain quite simple. Following the current guidelines, all patients with established coronary artery disease scheduled for CABG surgery need to be treated with statins before and after cardiac surgery unless otherwise contraindicated. Otherwise, untreated patients are deprived of a safe therapeutic option that reduces short-term and long-term cardiovascular mortality and morbidity. References 1. Bridgewater B, Gummert J, Walton P, Kinsman R. 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