A Multicenter Randomized Trial of Atorvastatin Therapy in Intensive Care Patients with Severe Sepsis

RATIONALE: Observational studies link statin therapy with improved outcomes in patients with severe sepsis. OBJECTIVES: To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis. METHODS: Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo. MEASUREMENTS AND MAIN RESULTS: There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P = 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P = 0.26). Baseline plasma IL-6 was lower among previous statin users (129 87-191 vs. 244 187-317 pg/ml; P = 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 0.07 vs. 2.6 0.06 mmol/L; P = 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%; P = 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%; P = 0.06). CONCLUSIONS: Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival. Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404).