Different classes of statins have varying effects on reducing sepsis mortality

   Sepsis, a pathogen-induced systemic inflammation that leads to organ dysfunction, remains a major public health problem. Each year, an estimated 20 to 30 million patients develop sepsis, and the annual incidence is still increasing in many countries. However, anti-infective therapy may not be sufficient for all sepsis patients and could give rise to antibiotic-resistant bacteria. Thus, strategies that can resolve inflammation or reverse immune paralysis associated with sepsis are intensively studied. To address this important disease that poses a great economic and healthcare burden, we explored nonantibiotic treatment options for sepsis in the population. First, we re-evaluated the effectiveness of statins, lipid-lowering agents with pleiotropic effects, including their anti-inflammatory and antimicrobial activity, on the outcome of sepsis. Although many studies have assessed the effectiveness of statins on sepsis, some basic problems have not been resolved. First, despite the efficacy demonstrated in animal and observational studies, clinical trials have revealed opposite results. Second, whether the beneficial effect of statins is derived from a “healthy user bias” has not been resolved. We designed our analysis to target these two unresolved problems. In the first study, we created the largest sepsis cohort in the literature, which allowed us to explore the effect of statins on different subpopulations. We found that (1) the effectiveness of statins requires a priming time before sepsis onset. Most clinical trials have used statins after sepsis onset, and potentially, a sufficient amount of time did not transpire to change the outcome within a few days of dosing. (2) The effect of preadmission statin use in sepsis patients is attenuated when the severity of sepsis increases. Less severe sepsis patients may receive greater benefit from statins than more severe patients. Most clinical trials were performed on sepsis patients requiring ICU admission and therefore may not observe the beneficial effects in a limited sample. This work was published in a top-ranked anesthesiology journal (M. G. Lee et al., 2017).
   In the second study, we analyzed subclasses of statins (C. C. Lee et al., 2017). If the effect of statins on the outcome of sepsis is drastically different for different subclasses of statins, then the results could provide strong evidence against the presence of a “healthy user bias”. Under the “healthy user bias” hypothesis, all subclasses of statins would exhibit similar effects on the sepsis outcome. The analysis revealed that, compared to atorvastatin or rosuvastatin, simvastatin has a significantly superior protective effect on sepsis patients (Figure 1). The results not only corroborate the findings from in vitro statin anti-antimicrobial experiments but also refute the possibility that a pure “healthy user bias” is responsible for the observed statin benefits in a large body of literature. Given that this breakthrough finding greatly alleviated concerns about the questionable benefits of statins on sepsis patients and highlighted a new direction for statin antisepsis research, our study won the “Best Abstract Award” of the prestigious European Society of Intensive Care Medicine. This was the first time that a Taiwanese team won this award (Figure 2).
   Professor Chien-Chang Lee leads the multinational and multidisciplinary research team at the National Taiwan University Hospital that conducted these studies. The team includes clinicians from Italy (Lorenzo Porta) and Taiwan (Yung-Ming Chen, Shy-Shin Chang, Chia-Hung Yo, and Kuang-Chau Tsai) who work to address unmet clinical needs. The team also includes a statistician (Tzu-Chun Hsu) and epidemiologists (Meng-tse Lee, and Kuo-Liong Chien) who analyze and interpret the data.
Figure 1. Cumulative hazard plot of mortality after propensity score matching. We created cumulative hazard plots based on three types of statin users in the propensity score-matched cohort. Compared to atorvastatin or simvastatin users, rosuvastatin users exhibit a significantly increased cumulative mortality at 90 days.
Figure 2. Best abstract award at the 2017 European Society of Intensive Care Medicine Conference. The work on the drug-specific effect of statins won the “Best Abstract Award” at the prestigious annual conference of the European Society of Intensive Care Medicine. There were approximately 450 submissions from more than 40 countries. This is the first time that a Taiwanese team won this award. 
1. Lee, C. C., Lee, M. G., Hsu, T. C., Porta, L., Chang, S. S., Yo, C. H., . . . Lee, M. (2017). A Population-Based Cohort Study on the Drug-Specific Effect of Statins on Sepsis Outcome. Chest, 153(4), 805-815. DOI:10.1016/j.chest.2017.09.024.
2. Lee, M. G., Lee, C. C., Lai, C. C., Hsu, T. C., Porta, L., Lee, M., . . . Chen, Y. M. (2017). Preadmission statin use improves the outcome of less severe sepsis patients-a population-based propensity score matched cohort study. British Journal of Anaesthesia, 119(4), 645-654. DOI:10.1093/bja/aex294
Chien-Chang Lee
Clinical Associate Professor, Department of Emergency Medicine, College of Medicine, National Taiwan University Hospital
Meng-tse Gabriel Lee
Postdoctoral Fellow, Department of Emergency Medicine, College of Medicine, National Taiwan University Hospital