Discussion
illness, sepsis, high-density lipoprotein reduction, ARDS
HYPOCHOLESTEREMIA, SIDE EFFECT, SECONDARY, SEPSIS, ARDS
This study first investigated the association between total cholesterol levels with mortality and secondly the response to statin therapy in patients with ARDS and sepsis through a secondary analysis of the SAILS and HARP-2 trials. These cohorts had remarkably low baseline cholesterol levels, and low cholesterol correlated with increased illness severity in both cohorts. Subjects with lower cholesterol had higher mortality when randomized to receive rosuvastatin in the SAILS cohort. In contrast, fewer patients with sepsis and ARDS with low cholesterol randomized to simvastatin died in the HARP-2 trial compared to those who received placebo, though this did not reach statistical significance.Median cholesterol level in our subsets with sepsis was 97 mg/dL in both SAILS and HARP-2, but perhaps more striking were the extreme values seen in the lowest quartile of total cholesterol, defined by < 69 mg/dL and < 44 mg/dL respectively. Higher rates of shock/vasopressor use are noted in HARP-2, which may indicate greater illness severity and thus contribute to the lower cholesterol levels seen in this trial. Reduced vascular tone has previously been associated with hypocholesteremia; however, the mechanism is not fully understood [The direction of effect of statin therapy on mortality differed, with rosuvastatin associated with increased mortality in patients with low cholesterol, while simvastatin non-significantly decreased mortality in the same subset. This discrepancy between the trials might be due to differences in the properties and doses of these two statins. Rosuvastatin (administered at a daily dose of 20 mg in SAILS) was selected for SAILS because of its lower side effect profile and reduced incidence of drug-drug interactions. However, simvastatin (administered at a daily dose of 80 mg in HARP-2) had been previously proposed as a superior statin medication for ARDS and sepsis despite its lower potency as a lipid-lowering agent (rosuvastatin 10 mg is equivalent to simvastatin 72 mg and 77 mg for low-density and high-density lipoprotein reduction, respectively) [Though the original SAILS and HARP-2 trials did not show benefit for either statin in the overall population studied, there remains interest in studying statins further in ARDS subphenotypes, given the encouraging data for simvastatin in highly inflamed subjects in particular [Our study has methodological strengths, including the inclusion of two independent randomized, controlled trial cohorts, which allows assessment of statin impact in a low cholesterol group without concern for confounding. Because the statin medications utilized in SAILS and HARP-2 were different, we have been able to capture within-class differences in effects of statin medications in ARDS. While the association between low cholesterol and bad outcomes in sepsis has been reported, consideration of total cholesterol as a potential predictor of response to statins has not been studied before in ARDS to our knowledge, and helps inform an area with plausible biological relevance.This study also has some weaknesses. First, despite including large RCT data, there was insufficient power to detect mortality differences which could be clinically significant. However, several models confirmed the mortality differences reported for low cholesterol subjects by treatment arm, and our observations of increased illness severity in low cholesterol subjects were also statistically significant by multiple tests. Secondly, the threshold for the lowest quartile differed in SAILS and HARP-2, and we did not define an optimal cholesterol threshold in this study. Third, cholesterol was not measured on fresh samples, but on stored aliquots years after study completion, and using two different assays for the two trials. We do note that our median values were similar not only to each other, but also to those described in the ANZ-STATInS trial [