A Population-Based Cohort Study on the Drug-Specific Effect of Statins on Sepsis Outcome

Lee, Chien‐Chang; Lee, Meng Tse Gabriel; Hsu, Tien-Pen; Porta, Lorenzo; Chang, Shy Shin; Yo, Chia‐Hung; Tsai, Kun-Tong; Lee, Matthew

doi:10.1016/j.chest.2017.09.024

Cited by 49 publications

(58 citation statements)

References 40 publications

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“…In a population-based study of sepsis, Lee and colleagues have recently shown reduced mortality at 30 days with prior use of simvastatin and atorvastatin but not rosuvastatin. [33] Extrapolating these data to SAILS, where the benefits of rosuvastin were tested in sepsis-associated ARDS, the assumption of class-effect with all statins may not be valid. The choice of a hydrophilic statin in SAILS may have contributed to the negative result in this study compared to the secondary analysis of HARP-2.…”

Section: Discussionmentioning

confidence: 99%

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

et al. 2018

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Purpose: Using latent class analysis (LCA), we have consistently identified two distinct subphenotypes in four randomized controlled trial cohorts of ARDS. One subphenotype has hyper-inflammatory characteristics and is associated with worse clinical outcomes. Further, within 3 negative clinical trials, we observed differential treatment response by subphenotype to randomly assigned interventions. The main purpose of this study was to identify ARDS subphenotypes in a contemporary NHLBI Network trial of infection-associated ARDS (SAILS) using LCA and to test for differential treatment response to rosuvastatin therapy in the subphenotypes. Methods: LCA models were constructed using a combination of biomarker and clinical data at baseline in the SAILS study (n=745). LCA modeling was then repeated using an expanded set of clinical class-defining variables. Subphenotypes were tested for differential treatment response to rosuvastatin. Results: The 2-class LCA model best fit the population. 40% of the patients were classified as the “hyper-inflammatory” subphenotype. Including additional clinical variables in the LCA models did not identify new classes. Mortality at Day 60 and Day 90 was higher in the hyper-inflammatory subphenotype. No differences in outcome were observed between hyper-inflammatory patients randomized to rosuvastatin therapy versus placebo. Conclusions: Using LCA, a 2-subphenotype model best described the SAILS population. The subphenotypes have features consistent with those previously reported in 4 other cohorts. Addition of new class-defining variables in the LCA model did not yield additional subphenotypes. No treatment effect was observed with rosuvastatin. These findings further validate the presence of two subphenotypes and demonstrates their utility for patient stratification in ARDS.

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Section: Discussionmentioning

confidence: 99%

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

et al. 2018

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“…Statins also showed a protective effect against sepsis. When compared with nonusers, simvastatin (HR, 0.72; 95% CI, 0.58-0.90) and atorvastatin (HR, 0.78; 95% CI, 0.68-0.90) users had improved 30-day survival [13]. The current study examined the anti-inflammatory effect of statins from a ventilation patient cohort, which has not been previously reported.…”

Section: Discussionmentioning

confidence: 87%

“…In pneumonia patients, current statin use was associated with decreased mortality [11] . Statin use or prior use may have decreased the mortality of septic patients in some observational studies [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Statin Use Is Associated With Reduced Mortality On Mechanically Ventilated Patients: A Retrospective Propensity-Matched Analysis Of MIMIC-III Database

Lin

Chen

et al. 2020

Preprint

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Objective: Mechanical ventilation can cause injury and inflammatory disorders in the lungs of critically ill patients. We sought to determine whether statin treatment has a protective effect on the outcome of these patients. Methods: A retrospective observational study of ICU patients from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Information on ventilated patients was analyzed using data from the MIMIC-III database. The non-statin cohort was selected using 1:1 propensity matching with the statin cohort by age, sex, severity scores and 29 other variables. Compared with nonusers, the use of statins was associated with improved 28-day survival in the unmatched cohort (HR 0.85 95% CI 0.80~0.90) and matched cohort (HR 0.72 95% CI 0.67~0.77). Statin use was also associated with improved in-hospital survival in both the unmatched cohort (HR 0.90, 95% CI 0.85~0.95) and the matched cohort (HR 0.75 95% CI 0.70~0.80). In the multivariate Cox model, the use of statins was also associated with an improvement in 28-day survival in the unmatched cohort (HR 0.73 95% CI 0.68～0.77) and in the matched cohort (HR 0.73 95% CI 0.68~0.78). The use of statins was associated with longer ICU length of stay (LOS), shorter ventilator-free days (VFDs) and fewer model for end-stage liver disease score (MELD) in the matched cohort. The subgroup analysis results showed improved 28-day survival, but this improvement was not observed in patients with pneumonia, obesity, septicemia or acute respiratory failure. Conclusions: In a population of mechanically ventilated patients, the use of statins may be associated with reduced mortality.

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“…Statins, hydroxymethylglutaryl‐CoA reductase inhibitors, may have effects on inflammatory diseases such as sepsis and ARDS via its multiple properties, including an anti‐inflammatory effect and inhibition of leucocyte adhesion . Statins have become a controversial treatment for sepsis and infectious diseases in recent years . Due to the poor water solubility and strong fat solubility of statins, NP carrier systems have been designed to enhance drug delivery, and it has been confirmed that SV‐NPs have good efficacy towards chronic inflammatory disorders such as atherosclerosis and chronic pulmonary disease .…”

Section: Discussionmentioning

confidence: 99%

“…35,36 Statins have become a controversial treatment for sepsis and infectious diseases in recent years. [36][37][38][39][40] Due to the poor water solubility and strong fat solubility of statins, NP carrier systems have been designed to enhance drug delivery, 41 and it has been confirmed that SV-NPs have good efficacy towards chronic inflammatory disorders such as atherosclerosis and chronic pulmonary disease. 29,42 The formulation of SV-NPs improves the pharmacokinetic profile and bioavailability of SV 43 ; it was also reported that nanostructured lipid carriers, especially those associated with SV, were able to reduce cytotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin preparations promote PDGF‐BB secretion to repair LPS‐induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway

Zheng

Zhang

Wang

2019

J Cellular Molecular Medi

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Endothelial barrier dysfunction is a critical pathophysiological process of sepsis. Impaired endothelial cell migration is one of the main reasons for endothelial dysfunction. Statins may have a protective effect on endothelial barrier function. However, the effect and mechanism of statins on lipopolysaccharide (LPS)‐induced endothelial barrier dysfunction remain unclear. Simvastatin (SV) was loaded in nanostructured lipid carriers to produce SV nanoparticles (SV‐NPs). Normal SV and SV‐NPs were used to treat human umbilical vein vascular endothelial cells (HUVECs) injured by LPS. Barrier function was evaluated by monitoring cell monolayer permeability and transendothelial electrical resistance, and cell migration ability was measured by a wound healing assay. LY294002 and imatinib were used to inhibit the activity of PI3K/Akt and platelet‐derived growth factor receptor (PDGFR) β. IQ‐GTPase‐activating protein 1 (IQGAP1) siRNA was used to knockdown endogenous IQGAP1, which was used to verify the role of the PDGFRβ/PI3K/Akt/IQGAP1 pathway in SV/SV‐NPs‐mediated barrier protection in HUVECs injured by LPS. The results show that SV/SV‐NPs promoted the migration and decreased the permeability of HUVECs treated with LPS, and the efficacy of the SV‐NPs exceeded that of SV significantly. LY294002, imatinib and IQGAP1 siRNA all suppressed the barrier protection of SV/SV‐NPs. SV/SV‐NPs promoted the secretion of platelet‐derived growth factor‐BB (PDGF‐BB) and activated the PDGFRβ/PI3K/Akt/IQGAP1 pathway. SV preparations restored endothelial barrier function by restoring endothelial cell migration, which is involved in the regulation of the PDGFRβ/PI3K/Akt/IQGAP1 pathway and PDGF‐BB secretion. As an appropriate formulation for restoring endothelial dysfunction, SV‐NPs may be more effective than SV.

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A Population-Based Cohort Study on the Drug-Specific Effect of Statins on Sepsis Outcome

Cited by 49 publications

References 40 publications

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study

Statin Use Is Associated With Reduced Mortality On Mechanically Ventilated Patients: A Retrospective Propensity-Matched Analysis Of MIMIC-III Database

Simvastatin preparations promote PDGF‐BB secretion to repair LPS‐induced endothelial injury through the PDGFRβ/PI3K/Akt/IQGAP1 signalling pathway

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