Statins are one of the most commonly prescribed medications in the world and represent the mainstay of therapy for lowering cholesterol in at-risk patients. Evidence has emerged from basic science research that 3-Hydroxy, 3-Methylglutaryl Coenzyme A (HMG-CoA) Reductase inhibitors (statins) have beneficial effects independent of their lipid lowering properties. These include anti-inflammatory and immunomodulatory roles that might be associated with a reduced mortality in sepsis.
This thesis describes a journey that includes a retrospective review of statin use in patients with bacteraemia, a prospective study of statin use and lipid profiles in critically ill patients with sepsis, a systematic review of clinical trials on statin use in sepsis, single dose pharmacokinetic studies of atorvastatin and rosuvastatin in critically ill patients and concludes by reporting the results of the largest published randomised controlled trial of statin use in patients with sepsis.
The retrospective study demonstrated a significant survival benefit associated with continuing statin therapy in bacteraemic patients. There was a significant reduction in all cause hospital mortality (10.6% vs. 23.1%, p=0.02) and death attributable to bacteraemia (6.1% vs. 18.3%, p=0.01) in patients who were receiving statin therapy at the time of bacteraemia (n=66).The apparent mortality benefit persisted after controlling for differences between the groups. Prior statin use was associated with a reduced adjusted hospital mortality rate (Odds ratio 0.39, CI 95 % 0.17, 0.91, p=0.03) and continuing statin use after bacteraemia increased this effect (Odds ratio 0.06, CI 95 % 0.01, 0.44, p=0.006).
This finding prompted the prospective study of statin use and plasma lipids in critically ill patients with suspected infection. Plasma lipid profiles are profoundly deranged in patients with infection with a very low HDL being commonly seen. HDL was lower inpatients with proven infection. Prior statin use did not appear to influence the lipid profile in patients with sepsis.
The preliminary pharmacokinetic studies of atorvastatin in patients with sepsis showed for the first time an unexpected and significant increase in plasma levels. Inhibition of hepatic cytochrome P450 3A4 enzymes may explain in part the increased plasma levels. A modest increase in plasma levels was also seen with rosuvastatin levels in patients with sepsis. As rosuvastatin is essentially not metabolised by CYP 3A4, this would suggest other factors are involved. Bilirubin level correlated with rosuvastatin plasma exposure. Further research is required to explore the significant inter-patient variability, possible causes of elevated plasma levels and the potential pharmacodynamic impact of these elevated levels.
The Continued use of Atorvastatin in Sepsis trial (CAS Trial) prospectively evaluated more than 2,000 patients admitted to hospital with presumed infection. No clinically significant difference in manifestations of inflammation (SIRS criteria) or hospital outcomes was seen between patients taking prior statin therapy and those not usually on a statin. Eligible patients taking statin therapy prior to hospitalisation were randomised to continue atorvastatin (n= 75) or matched placebo (n=75). The primary endpoint was the progression of sepsis during hospitalisation. No significant differences existed in the rate of decline of severe sepsis between the groups (Odds Ratio 1.17 [0.56- 2.47], p=0.7 day 3 and 0.85 [0.21 – 3.34], p=0.8 day 14). Interleukin-6 and C-Reactive Protein declined in both groups with no statistically significant difference between the groups (p=0.7, p=0.2 respectively). An increase in cholesterol occurred in the placebo group (p<0.0001). Hospital mortality for the cohort was 6.6 % with no difference between the groups (6 / 75 [8%] statin group, 4 / 75 [5.3%] placebo group, p= 0.75).
In this study, cessation of established statin therapy was not associated with a rebound of the inflammatory response. Continuing pre-existing statin therapy in patients hospitalised for presumed infection was not associated with improved sepsis outcomes or inflammatory parameters.
This randomised trial suggests some of the findings of retrospective data maybe the result of confounding. Statin users and non-users represent different populations in regard to age and co-morbid disease but also likely hidden potential confounders.
This work has established that enteral administration of statins to critically ill patients is possible. Interestingly, it can result in higher plasma levels than seen in the general population. Large inter-patient variability exists and further work is required to better explain the potential sources of variation and the biological consequences of these elevated plasma levels in patients with infection. It is possible statins may have differing biological effects at these higher levels to those seen at conventional plasma concentrations.
The body of work described in this thesis has led directly to a successfully funded, multicentre randomised trial of atorvastatin as an adjuvant therapy for sepsis (STATInS trial). I was the principle investigator of this trial and it has now been completed.