Preoperative statin is associated with decreased operative mortality in high risk coronary artery bypass patients

The use of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors (statins) has been shown to reduce death, myocardial infarction and stroke in patients with elevated serum cholesterol and in those with near normal serum cholesterol levels [1]. The mechanism of this improvement is likely multifactorial, with some benefit attributed to lipid lowering effects and some to lipid-independent (pleiotropic) properties. Recently, evidence has accumulated that statins have beneficial effects on various portions of the clinical pathway that leads to atherosclerosis and cardiovascular events. These effects include downregulation of the inflammatory cascade [2], stabilization of the endothelial cell [3], attenuation of oxidative damage [4], decreasing thrombotic risk and possibly plaque stabilization [5]. The use of statins has steadily increased over time, but these drugs remain under utilized, relative to the larger population at risk for atherosclerosis. Patients who require coronary artery bypass grafting (CABG) represent a small segment of the entire population of patients with coronary artery disease. Many CABG patients have been treated with statins as outpatients before CABG, but a sizeable group present with no previous statin therapy. This study was undertaken to examine the efficacy of preoperative statin use on in-hospital mortality after CABG surgery.

Multivariate regression analysis was also performed using composite postoperative major morbidity as an endpoint. Statin usage was not shown to have a significant impact on composite major morbidity in this limited assessment.

Statins are one of the most effective medicines introduced in the past 25 years. Nonetheless they are still relatively under prescribed, especially in patients without symptomatic or obvious atherosclerosis and those without severe hypercholesterolemia. Recently, our knowledge regarding the biology of the non-lipid lowering, or pleiotropic effects of statins has rapidly expanded. Simultaneously, a number of recent reports have suggested a salutary effect of statins on perioperative mortality for patients undergoing CABG.

Clark, et al, reported a retrospective database study from the Medical University of South Carolina covering 3829 patients between 1996 and 2002 [8]. Only 1044/3829 patients received preoperative therapy (28%). In a propensity matched analysis they demonstrated significant association between preoperative statin therapy and lower 30 day mortality and morbidity. These findings paralleled those of an earlier study by Pan et al from the Texas Heart Institute [9]. This study evaluated 1563 patients who underwent CABG with CPB at a single institution. Multivariate analysis was used to show a 50% reduction in the risk of perioperative (30 day) death in those patients who received statins preoperatively. The use of statins preoperatively was not associated with a lower incidence of post-operative complications. In a propensity matched subgroup analysis statin therapy was associated with a significantly lower risk of the composite endpoint including death and stroke (but not death alone).

Collard, et al, showed similar results in a large international, multi-institutional study [10]. The primary study was a longitudinal analysis of 5436 patients at 70 centers undergoing CABG. The statin study was a post-hoc retrospective analysis using this database and showed reduced early cardiac mortality in patients receiving statins who underwent elective CABG (0.3% vs. 1.4%). Further, the discontinuation of statins post-operatively was associated with increased all-cause hospital mortality (2.6% vs. 0.6%) compared to those who had statin therapy maintained.

Statin use in the current study averaged 42% (range 38 - 46%) over the five-year period of 2000-2004. The relatively low prevalence may represent a referral bias in that our center is a primary angioplasty referral center. Consequently, many patients have a new diagnosis of coronary artery disease and the statin is not always started before operation, especially in the urgent or emergent situation. Beginning in 2005 our isolated CABG population demonstrated an increase in preoperative statin use to greater than 80%.

The most important objective of this study was to determine if the use of preoperative statin therapy is associated with reduced postoperative mortality. In each of the 5-years of the study, the mortality rate was lower in the group of patients exposed to statins preoperatively (range 26 - 60%.) In total, the net effect was to reduce mortality from 2.8% to 1.7%. The effect was seen in all groups, but was most notable in the high risk cohort (12.9% vs. 5.6%, p < 0.05), where the predicted mortality was 6% and higher.

This study was not designed to explain how statins exert their salutary effect. Nonetheless, a number of hypotheses are generated. Our group [11] and others [12] have recently shown that patients undergoing heart surgery who have elevated risk based on standard preoperative variables (age, left ventricular dysfunction, co-morbid disease) have evidence of ongoing inflammation manifested by elevated levels of inflammatory mediators such as interleukin-6 (IL-6) and C-reactive protein (CRP). Statins have been shown to ameliorate the inflammatory cascade in a number of models and these properties may confer protection from the inflammatory response induced by open heart surgery. This may explain the more pronounced protective effect of statins in our high risk cohort.

Statins have also been shown in clinical trials to be associated with decreased mortality when administered in the first 24 hours after acute myocardial infarction [13, 14]. This may be the result of their potential ability to limit infarct size, as demonstrated in animal models of acute infarction [15]. These properties may contribute to the beneficial effect associated with CABG and would help to explain the more marked effect in high risk patients, many of whom require urgent or emergent surgery in the setting of acute ischemia or infarction.

The current study, in addition to all the other studies on preoperative statin use, is retrospective and nonrandomized. This introduces the issue of selection bias and other confounding variables. The statistical analysis minimizes this possibility, but it cannot eliminate this issue completely. Further, we do not have specific information regarding the specific statin, dose, duration or cholesterol lowering efficacy. There may be important factors with regard to dosage and duration of therapy that impact the benefit of statins in this patient population that we can not identify with this study. Nonetheless, we have shown a consistent reduction in perioperative mortality in patients being treated with statins, particularly those with elevated operative risk. While placebo controlled trials will likely not be possible, further study of the underlying mechanisms of these effects are needed.