RCCT of Atorvastatin in Reducing the Severity of Sepsis
RCCT of Atorvastatin in Reducing the Severity of Sepsis
Introduction: Several observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis.
Methods: A single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization.
Results: 100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238).
Conclusions: Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings.
Trial Registration: International Standard Randomized Control Trial Registry ISRCTN64637517.
Sepsis describes a complex clinical syndrome that results from a harmful or damaging host response to infection. It is commonly seen in hospital emergency departments and wards with an estimated prevalence of 15% in the UK. A significant proportion of patients with sepsis go on to develop severe sepsis or septic shock with associated mortality rates of up to 50%. Despite considerable research there still remains a lack of targeted pharmacological interventions to treat and improve outcomes from sepsis.
Statins inhibit 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. They are well established in the prevention of cardiovascular disease and have been shown to exert numerous effects in addition to their lipid-lowering properties. These pleiotropic properties include anti-inflammatory and immunomodulatory effects resulting in improved endothelial function, reduced thrombogenicity and plaque stabilisation.
The inflammatory and immune response provoked by sepsis could potentially be modulated by statins via these pleiotropic effects. Several systematic reviews have concluded that statins have a role in improving infection-related outcomes and mortality but most of this evidence comes from retrospective and prospective observational studies. In a prospective cohort study of 361 patients it was reported that patients already receiving statin therapy had reduced rates of severe sepsis and intensive care admissions. So far there have been only two published randomized controlled trials (RCTs) investigating the role of statins in sepsis. One of these, a double-blind RCT to assess whether acute administration of statins reduced sepsis progression and cytokine production was stopped prematurely due to slow recruitment and was unable to analyse data relating to sepsis conversion. There were significantly decreased levels of IL-6 and TNF-α at 72 hours, however, compared with baseline (P = 0.02). A more recent RCT investigated whether continuation of pre-existing statin therapy prevented conversion of sepsis to severe sepsis. It concluded that continuation of statin therapy did not reduce progression of sepsis or the development of organ failure and that the witholding of statin therapy did not result in any inflammatory rebound.
The recent withdrawal from the market of recombinant activated protein C (drotrecoginalfa, rhAPC) following the results of the PROWESS-Shock trial has resulted in there being no specific therapy for sepsis other than source control and antibiotics. Statins offer a safe multi-modal mechanism to target the inflammatory and immunological cascade of sepsis which could be prescribed to patients prior to the establishment of septic shock.
The aim of this study was to evaluate whether the acute use of atorvastatin 40 mg/day in ward patients with sepsis would significantly reduce rates of conversion of sepsis to severe sepsis (≥ one organ failure) compared with placebo in patients not previously treated with statins.
Abstract and Introduction
Abstract
Introduction: Several observational studies suggest that statins modulate the pathophysiology of sepsis and may prevent its progression. The aim of this study was to determine if the acute administration of atorvastatin reduces sepsis progression in statin naïve patients hospitalized with sepsis.
Methods: A single centre phase II randomized double-blind placebo-controlled trial. Patients with sepsis were randomized to atorvastatin 40 mg daily or placebo for the duration of their hospital stay up to a maximum of 28-days. The primary end-point was the rate of sepsis progressing to severe sepsis during hospitalization.
Results: 100 patients were randomized, 49 to the treatment with atorvastatin and 51 to placebo. Patients in the atorvastatin group had a significantly lower conversion rate to severe sepsis compared to placebo (4% vs. 24% p = 0.007.), with a number needed to treat of 5. No significant difference in length of hospital stay, critical care unit admissions, 28-day and 12-month readmissions or mortality was observed. Plasma cholesterol and albumin creatinine ratios were significantly lower at day 4 in the atorvastatin group (p < 0.0001 and p = 0.049 respectively). No difference in adverse events between the two groups was observed (p = 0.238).
Conclusions: Acute administration of atorvastatin in patients with sepsis may prevent sepsis progression. Further multi-centre trials are required to verify these findings.
Trial Registration: International Standard Randomized Control Trial Registry ISRCTN64637517.
Introduction
Sepsis describes a complex clinical syndrome that results from a harmful or damaging host response to infection. It is commonly seen in hospital emergency departments and wards with an estimated prevalence of 15% in the UK. A significant proportion of patients with sepsis go on to develop severe sepsis or septic shock with associated mortality rates of up to 50%. Despite considerable research there still remains a lack of targeted pharmacological interventions to treat and improve outcomes from sepsis.
Statins inhibit 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting enzyme in the biosynthesis of cholesterol. They are well established in the prevention of cardiovascular disease and have been shown to exert numerous effects in addition to their lipid-lowering properties. These pleiotropic properties include anti-inflammatory and immunomodulatory effects resulting in improved endothelial function, reduced thrombogenicity and plaque stabilisation.
The inflammatory and immune response provoked by sepsis could potentially be modulated by statins via these pleiotropic effects. Several systematic reviews have concluded that statins have a role in improving infection-related outcomes and mortality but most of this evidence comes from retrospective and prospective observational studies. In a prospective cohort study of 361 patients it was reported that patients already receiving statin therapy had reduced rates of severe sepsis and intensive care admissions. So far there have been only two published randomized controlled trials (RCTs) investigating the role of statins in sepsis. One of these, a double-blind RCT to assess whether acute administration of statins reduced sepsis progression and cytokine production was stopped prematurely due to slow recruitment and was unable to analyse data relating to sepsis conversion. There were significantly decreased levels of IL-6 and TNF-α at 72 hours, however, compared with baseline (P = 0.02). A more recent RCT investigated whether continuation of pre-existing statin therapy prevented conversion of sepsis to severe sepsis. It concluded that continuation of statin therapy did not reduce progression of sepsis or the development of organ failure and that the witholding of statin therapy did not result in any inflammatory rebound.
The recent withdrawal from the market of recombinant activated protein C (drotrecoginalfa, rhAPC) following the results of the PROWESS-Shock trial has resulted in there being no specific therapy for sepsis other than source control and antibiotics. Statins offer a safe multi-modal mechanism to target the inflammatory and immunological cascade of sepsis which could be prescribed to patients prior to the establishment of septic shock.
The aim of this study was to evaluate whether the acute use of atorvastatin 40 mg/day in ward patients with sepsis would significantly reduce rates of conversion of sepsis to severe sepsis (≥ one organ failure) compared with placebo in patients not previously treated with statins.
Source...