Statins for sepsis: has their time come?

Crit Care Med 2012 Vol. 40, No. 4 Sepsis is the 11th leading cause of death overall in the United States and despite advances in its treatment, sepsis continues to cause a huge number of deaths (1). Therefore, new additional therapies for sepsis are a priority. Statins or 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitors are extensively used as lipidlowering agents for primary and secondary prevention of cardiovascular disease. In addition, statins exert immunomodulatory and anti-inflammatory actions, referred to as pleiotropic effects, which are mostly independent of lipid-lowering and seem to be mediated by disrupting the synthesis of the isoprenoid derivatives of mevalonate and subsequent geranylation of membrane proteins. These effects make statins investigational and promising drugs for an increasing number of disorders, including severe infection and sepsis. In this issue of Critical Care Medicine, Leung et al (2), however, report that the use of statins is not associated with improved survival in patients with bloodstream infection. Bacteremia is a fundamental pathophysiological determinant of sepsis, which is referred to as a process of malignant intravascular inflammation that permits the extension of a normal pathophysiological response to infection to involve otherwise normal tissue. The mechanisms by which statins reduce sepsis-associated inflammation are not completely understood. The experimental benefits of statins in sepsis could be mainly mediated through their effects on cell signaling with consequent changes at the transcriptional level, the induction of heme oxygenase, the direct alteration of leukocyte–endothelial cell interaction, and the reduced expression of major histocompatibility complex II (3). In animal models of sepsis, treatment with statins has been reported to improve outcome, providing the biological plausibility for studies in human beings. The effect of statins in sepsis has been evaluated in several prospective and retrospective observational studies. Two systematic reviews and meta-analysis (4, 5) plus a systematic review (6) on severe infections and sepsis have recently been published. In the latest of these metaanalysis, Janda et al (5) demonstrated a significant protective effect on various infection-related outcomes for statins in patients with sepsis and/or infection compared with placebo, including bacteremia-related mortality in four studies and sepsis-related mortality in another four studies. These encouraging results, however, are limited by the design of the selected studies. Only one study was a randomized controlled trial (7), in which sepsis-related outcomes were not the primary end point, and 12 of 19 cohort studies were retrospective with a limited ability to control confounding variables. In contrast, this year one retrospective observational study in severe sepsis and septic shock (8) and two prospective observational studies in pneumonia (9) and bloodstream infections in immunosuppressed patients (10) found no benefit in the use of statins on clinical outcomes. Kruger et al (11) recently published a randomized controlled trial of atorvastatin (20 mg) or matched placebo in 150 patients on pre-existing statin therapy requiring hospitalization for infection. They reported no benefit in the continuation of treatment with statins on the progression of sepsis and inflammatory parameters. None of these studies evaluating the effects of statins provided information on side effects of statins. The risks associated with statin therapy may be increased for septic patients and so need to be examined. The study by Leung et al (2) is a retrospective cohort propensity-matched study of the effects of statins on 90-day all-cause mortality in 2139 hospitalized adult patients with bloodstream infection. An initial association was found in the unmatched cohort between ongoing treatment with statins and mortality (odds ratio 0.78; 95% confidence interval 0.65–0.94), but it disappeared when a rigorous propensity assay was applied to balance the differences in baseline clinical factors between groups (odds ratio 0.96; 95% confidence interval 0.70–1.06), pointing out how results can change after controlling confounding variables. Statins were also not associated with any of the secondary outcomes in the propensity-matched cohort: reduced intensive care unit admission, hospital length of stay, intensive care unit length of stay, and the need for mechanical or noninvasive ventilation. The authors included in the propensity score calculation a large number of important variables associated with statin use and the outcome. The matching process eliminated all significant differences that existed between groups with the sole exception being the higher percentage of patients receiving antibiotics within 6 hrs at the time of bacteremia in the nonstatin group. A significant aspect of the study is that the number of patients with bacteremia who received statins in the study (n = 447 in the matched cohort) is much higher than those previously published by other authors (10, 12–15). It is also significant that when the authors performed a sensitivity analysis including only patients with sepsis (78%), which is the hypothetical reason for using statins in severe infections, there was no benefit in the use of statins on survival. It is worth noting that this study included the types of statins used as well as other cardiovascular medications such as aspirin, which could improve the protective effects of statins in severe sepsis (16). The study has certain limitations; some important confounding variables such as septic shock and inadequate empirical antimicrobial treatment were not included; the dose of statin was not analyzed and the duration of prehospital statin therapy were unknown. Besides, the observational design of the study does not allow the inference of causality. Despite these limitations, the study by Leung et al (2) adds relevant knowledge about the use of statins in bloodstream infections. Statins for sepsis: Has their time come? *