Statins in patients with sepsis and ARDS: is it over? We are not sure.

Abstract

Statins are lipid-lowering agents which act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase and are generally used for cardiovascular prevention. Statins, however, also present anti-inflammatory and immunomodulating effects which could be of interest in sepsis and acute respiratory distress syndrome (ARDS). Many experimental investigations and some epidemiological studies support this theoretical beneficial effect. However, recent interventional studies which showed no benefit have been discouraging and do not support the use of statins in septic and/or ARDS patients. The mechanism of action in sepsis remains uncertain. Some data suggest that expression of Toll-like receptors could be downregulated, while others showed that mitochondria turn over could be promoted leading in turn to enhancement of antimicrobial host defence [1, 2]. However, it is still unclear to what extent inhibiting or at least mitigating the host inflammatory response could actually prevent sepsis mortality outside experimental conditions. Moreover, although a number of publications have raised the possibility that statins could exert protective effects in sepsis, their retrospective design makes it difficult to control for potentially “protective” confounders, especially the so-called healthy user effect [3]. Randomized clinical trials published so far failed to demonstrate a positive effect [4]. In addition, none of these studies reported evidence supporting an antiinflammatory effect of statins, suggesting that this could not be achieved with the recommended treatment regimen. Increasing doses could, however, be hazardous given the risk of adverse effects such as liver toxicity. However, patients with prior exposure to statins randomised to the treatment group had an improved outcome in one randomised controlled trial [5]. One could hypothesize that in those patients statins exert a “preventive” effect against the risk of an overwhelming inflammatory response from the host once subjected to an infectious insult. Accordingly, it has been shown that post-operative infectious complications were less likely in previous statin users [6]. Similarly, exposure to statins prior to the development of ventilator-associated pneumonia (VAP) was associated with a lower mortality rate, whereas they were ineffective when started once VAP was clinically overt [7, 8]. Altogether these findings suggest that statins should not be recommended as adjunctive therapy in septic patients, although a protective effect cannot be excluded if therapy is given prior to the infection onset. The risk of toxicity should, however, be considered even if simvastatin 60 mg per day during 28 days was not associated with an increased rate of side effects as compared with the placebo group in a randomised controlled trial performed in mechanically ventilated patients presenting with a suspicion of VAP [8]. Despite recent improvements in the outcome of ARDS, pharmacological therapy for these patients remains limited. As for sepsis, data from recent large, multicentre, double-blind, randomised, placebo-controlled clinical trials in patients with ARDS have shown that, despite promising findings in preclinical and early phase clinical trials [9, 10], statins did not significantly improve clinical outcomes [11, 12]. When secondary endpoints were analysed, rosuvastatin was associated with a small decrease in liver and renal failure-free days [13]. Although simvastatin was associated with an increase in adverse events in ARDS patients, there was no increase in serious adverse events [12]. An individual patient data meta-analysis is planned to quantify the safety and efficacy of statin therapy in ARDS (http://www.crd.york.ac.uk/PROSPERO/ *Correspondence: laurent.papazian@ap‐hm.fr 4 URMITE UMR CNRS 7278, Hopital Nord, Reanimation des Detresses Respiratoires et Infections Severes, Aix‐Marseille Univ, APHM, 13015 Marseille, France Full author information is available at the end of the article